Book GoodPracticeInPediatricAndAdol

Good Practice in
Pediatric and
Adolescent Gynecology
Anna Maria Fulghesu

Editor
123
Good Practice in Pediatric and Adolescent
Gynecology
Anna Maria Fulghesu
Editor
Good Practice in Pediatric

and Adolescent
Gynecology
Editor
Anna Maria Fulghesu
Department of Obstetrics and Gynecology
University of Cagliari
Cagliari
Italy
ISBN 978-3-319-57161-4 ISBN 978-3-319-57162-1 (eBook)

https://doi.org/10.1007/978-3-319-57162-1
Library of Congress Control Number: 2017954378
© Springer International Publishing AG 2018

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Preface
This book is a very useful text to consult when a specific gynecological problem
affects a child or a young girl who needs your help.
This text is focused on a special time of women’s lives when the prevention of
sexual and reproductive problems is very important, and it is aimed at clinical pedia-
tricians and gynecologists. Each author is an expert scientist in the field, a member
of the Italian Society of Gynecology of Childhood and Adolescence (SIGIA), and
every chapter reports the most up-to-date knowledge. The text has a strong practical
relevance, and represents the guidelines of this scientific society.
The order of the chapters follows the age of girls from infancy, with genital mal-
formations, vulvovaginitis, to puberty, studying delayed puberty and postpubertal
gonadal failure.
Menstruation disorders, such as dysmenorrhea, heavy menstrual bleeding, men-
strual irregularities, eating disorders and polycystic ovary syndrome, are studied in
depth in individual chapters.
The prescription of contraceptives and the diagnosis and treatment of ovarian
cysts are specifically tailored to the adolescent age.
Sexual mutilation and abuse are also dealt with, and how to prevent, diagnose,
and treat the most frequent sexually transmitted diseases.
Finally, pregnancy in adolescence, which represents a difficult clinical responsi-
bility for gynecologists because of the high frequency of pregnancy-related disor-
ders, is described.
Happy reading!
Cagliari, Italy Anna Maria Fulghesu
v
Contents
1 Vulvovaginitis in Childhood�� 1
Cristina Vezzani, Gilda Di Paolo, Terryann Spagnuolo,
and Gabriele Tridenti
2 Delayed Puberty �� 19
Metella Dei and Francesca Pampaloni
3 Diagnosis and Treatment of Genital Malformations in Infancy
and Adolescence �� 35
Tiziano Motta and Chiara Dallagiovanna
4 Gonadal Failure�� 63
Maria Francesca Messina and Alfonsa Pizzo
5 Dysmenorrhea�� 77
Gabriele Tridenti and Cristina Vezzani
6 Dysfunctional Uterine Bleeding�� 99
Tiziano Motta, Antonio Simone Laganà,
and Salvatore Giovanni Vitale
7 Menstrual Disorders in Post-menarcheal Girls�� 117
Francesca Pampaloni and Pina Mertino
8 Eating Disorders in Adolescence�� 131
Vincenzina Bruni and Metella Dei
9 Diagnosis of Polycystic Ovarian Syndrome in Adolescence�� 143
Anna Maria Fulghesu, Cristina Porru, and Elena Canu
10 Recommendations for the First Prescription
of Hormonal Contraception in Adolescence�� 161
Floriana Di Maggio and Gilda Di Paolo
11 Ovarian Cysts in Adolescence�� 171
M. Chiara Lucchetti
12 Female Genital Mutilations�� 183
Lucrezia Catania, Omar Abdulcadir, and Jasmine Abdulcadir
vii
viii Contents
13 Sexual Abuse and Genital Trauma�� 193

Maria Rosa Giolito, Giulia Mortara, and Monica D’Amato
14 Sexually Transmitted Diseases in Adolescence�� 211
Gilda Di Paolo
15 Pregnancy in Adolescence �� 239
About the Author
Anna Maria Fulghesu is a medical doctor specializing in obstetrics and gynecol-

ogy. As researcher of Obstetrics and Gynecology, from 1988 until 2000, she worked
in the Department of Obstetrics and Gynecology at the Sacred Heart of Rome
(Policlinico Gemelli), and since 2000 in Cagliari as Associate Professor at the
Università degli Studi. She is founder and is responsible for the Outpatient Service
of Pediatric and Adolescent Gynecology (PAG) in Calgliari. At the same hospital,
she has been involved in the Sexual Abuse Service in Childhood and Adolescence.
As an invited speaker, she has taken part in several national and international events.
As a teacher, she has given her services on many courses for medical doctors and
health caregivers. She has herself organized several courses on PAG, including six
national day courses. Author of more than 100 published scientific papers, she is
also a referee for several national and international scientific journals and she is a
member of the following scientific societies:
–– International Federation of Infantile and Juvenile Gynecology (FIGJI)
–– Società Italiana di Ginecologia dell’Infanzia e dell’Adolescenza (SIGIA, Italian
Society of Gynecology of Childhood and Adolescence): executive board mem-
ber since 2013.
ix
Vulvovaginitis in Childhood
1
Cristina Vezzani, Gilda Di Paolo, Terryann Spagnuolo,
and Gabriele Tridenti
1.1 Introduction
Vulvovaginal complaints account for 80–90% of outpatient pediatric gynecologic

visits [40]. Most cases may be attributed to vulvovaginitis but other less common
conditions, such as vulvar diseases or vulvar manifestations of systemic disease,
should be taken into account. Rare causes of vulvovaginitis have to be considered
especially when symptoms are recurrent or not responsive to standard treatment. In
this chapter, the causes, manifestations, and management options of vulvovaginitis
in childhood will be reviewed. Furthermore, common vulvar diseases affecting chil-
dren were outlined, since their knowledge is essential for differential diagnosis. The
prepubertal child is particularly susceptible to vulvovaginitis for anatomic, physio-
logic, and behavioral factors: absence of hair and minimal labial development; close
proximity of the vagina to the anus; physiological hypoestrogenism which causes
atrophic genital mucosa; neutral pH and unbalanced vaginal flora; absence of cervi-
cal mucus; and lack of antibodies [1]; furthermore, children’s tendency to have poor
local hygiene and to explore their bodies increases the risk of developing this condi-
tions. Germs may easily reach the genital area as a result of contiguity from the
rectum, urethra, or the surrounding skin. Diffusion of bacteria from the upper
C. Vezzani, M.D. • G. Tridenti, M.D.

Department of Obstetrics and Gynaecology, Santa Maria Nuova Hospital-IRCCS,
Reggio Emilia, Italy
e-mail: [email protected]; [email protected]
G. Di Paolo, M.D. (*)
Pediatric and Adolescent Gynecology Service, Department of Gynaecology and Obstetrics,
Santo Spirito Hospital, Pescara, Italy
e-mail: [email protected]
T. Spagnuolo, M.D.
Studio Madreperla, Pescara, Italy
© Springer International Publishing AG 2018 1

A.M. Fulghesu (ed.), Good Practice in Pediatric and Adolescent Gynecology,
https://doi.org/10.1007/978-3-319-57162-1_1
2 C. Vezzani et al.
airways is also possible through autoinoculation and occasionally hematic spread

[2]. Obesity, diabetes, anatomic anomalies, and use of antibiotics may play a role in
facilitating vulvovaginitis.
1.2 Etiology
Vulvovaginitis are easily classified into two groups on the basis of etiology [3]
• Nonspecific
• Specific
Nonspecific vulvovaginitis refers to vulvovaginal irritation without an identifi-

able pathogen, accounting up to 25–75% of all cases of vulvovaginitis in children
[4]. Symptoms may often be caused by irritative-allergic reaction to topical or food
agents, nickel, or by poor perineal hygiene. Vaginal cultures are usually negative or
positive for skin flora/anaerobes/enteric organism [5]. However, in many cases eti-
ology cannot be found.
Specific vulvovaginitis are caused by specific pathogens. It has been reported
that infective vulvo vaginitis were found in one-third of young girls presenting with
vulvovaginitis [6]. Infectious may be caused by bacterial agents, pinworms, viruses,
and sexually associated pathogens.
Knowledge of the normal vaginal microflora in prepubertal age is an essential
prerequisite for definition of the pathogens of the lower genital tract and will limit
the overtreatment of non-pathogens (lactobacilli, diphtheroids, alpha-hemolytic
streptococci) [7].
It has been reported that some microorganisms, other than those traditionally
considered part of normal flora, can be isolated from vaginal culture of girls without
symptoms (Escherichia coli, Candida, Staphylococci, enterococci, Streptococcus
viridans, Streptococcus agalactiae, Corynebacterium, Proteus Mirabilis,
Pseudomonas aeruginosa). As these organisms are present in healthy prepubertal
girls, their growth in culture is not diagnostic [8]. Many of those bacteria may spread
from skin or bowel and may act as opportunistic pathogens and cause infection
only when the child has a temporary immune system depression. Escherichia coli
and Candida may be present in vaginal flora, respectively, in 8 and 4% of asymp-
tomatic patient populations [7]. Clinician should consider that Candida infection is
unlikely unless the girl has predisposing factors: recent antibiotic use, diabetes mel-
litus, immunodeficiency syndromes, poor perineal aeration, inflammatory skin con-
ditions such as diaper dermatitis, seborrheic dermatitis, and atopic dermatitis [9].
Escherichia coli and other enteric opportunistic microorganisms typically spread
from intestinal tract after pinworm infestation or poor hygiene or dysfunctional
intestinal disorders. Staphylococcus aureus may cause opportunistic skin infections
which may appear as impetiginous, bullous, or suppurative.
The non-sexually transmitted pathogens responsible for vulvovaginitis are repre-
sented by respiratory pathogens such as group A beta-hemolytic Streptococcus
1 Vulvovaginitis in Childhood 3
(Streptococcus pyogenes), Haemophilus influenzae, Streptococcus and

Staphylococcus pneumonia, Staphylococcus aureus, Branhamella catarrhalis,
Neisseria meningitidis and enteric pathogens such as Shigella, and Yersinia [7].
Streptococcus pyogenes and Haemophilus influenzae, transferred from the upper
respiratory tract, are the two most common causative agents, in both primary care
settings and referral populations [10, 11]. Shigella and Yersinia typically cause diar-
rhea, therefore in some cases vulvovaginitis may be associated.
Another frequent cause of vulvovaginitis is pinworm (Enterobius vermicularis)
infestations. Pinworms are helminths that commonly cause vulvar and perianal pru-
ritus. Female pinworms lay eggs at night around the anus and vulva. The mature
worms may carry colonic bacteria to the perineum, causing recurrent vulvovagini-
tis. E. coli is common with spread of the pinworms from the anus to the vagina [12].
The most common genital viral infections in childhood are Molluscum conta-
giosum, Papilloma virus, and Herpes simplex.
Vulvovaginal complaint may be attributed, other than vulvovaginitis, to: foreign
body, polyps and tumor of cervix/vagina, systemic illness (measles, chickenpox,
scarlet fever, mononucleosis, Crohn disease, Kawasaki disease, histiocytosis), ana-
tomic anomalies (double vagina, fistula, pelvis abscess, ectopic ureter, prolapsed
urethra), vulvar skin disease, and psychosomatic complaints [7].
1.3 History
The first step to diagnosis is to spend time obtaining the history. As vulvovaginitis
could be associated to a large number of conditions, a detailed anamnesis is very
important in narrowing the etiology and directing treatment. Information can be
obtained from parents and, when age allows, from the child. Questions should focus on
the onset, duration, characteristic and localization of symptoms, history of skin disease
or systemic disease, allergic diathesis (atopic dermatitis, asthma, rhinitis), allergies to
medications, autoimmune disease, urogenital and anorectal malformation, recent ill-
ness and treatment (antibiotics, corticosteroids, immunomodulators drugs). A list of
possible acute or chronic irritant exposures such as bubble baths, cleaning agents,
lotions, powders, fabric softeners, and hair products should be investigated. Family
history of chronic illness, allergies, and contact sensitivities are also important.
Information on perineal hygiene habits, urinary or intestinal dysfunctions, incor-
rect behavior when urinate and defecate, practice of cycling or horsing, sexual activ-
ity, and masturbatory activity should be elicited. Social contest, psychological
distress, and the possibility of sexual abuse also must be considered.
1.4 Physical Examination and Diagnostic Testing
The examination of the child presenting with gynecologic complaints should

include systemic physical assessment and genital inspection. It is important to
invest time in communication, explaining parents and patients, when age is
4 C. Vezzani et al.
appropriate, the examination techniques and that the procedure will be painless.
Interpersonal and communication skills, time, and adequate setting are required to
achieve good relationship with parents and girls. General examination should be
focused on observing signs of dermatological conditions such as allergic reactions
or dermatitis. Genital examination can be performed in most cases without sedation
or anesthesia. The ideal position for good visualization of external genitalia is
supine with legs in the “frog leg position.” The genupectoral position may be useful
in some cases. In order to assess the introitus and the lower third of the vagina, fin-
ger may be used to gently grasp labia laterally and downward or anteriorly. The
magnification of either an otoscope or a colposcope or a hand lens facilitates the
examination. The appearance of female genitalia varies through ages, whereas hor-
monal changes induced by maternal estrogenization or puberty may have remark-
able influences on the skin. Practitioners have to deal with various genital features
in newborn infant, prepubertal and peripubertal girls. Specific knowledge of anat-
omy and physiology of genital system and experience in pediatric gynecology are
required to recognize normal genital anatomy since normal findings are poorly
described in the evidence-based literature and wide variability in appearance of
genitalia among individuals may be confounding factor.
The clinician should describe Tanner stage of breast and pubic hair, size and
configuration of clitoris, configuration of hymen, labia, urethra meatus, sign of
estrogenization, perineal hygiene, anatomic anomalies (dislocation of urethral or
anal openings, signs of suspected vescicovaginal or enterovaginal fistulae), vulvar
and perianal skin conditions, and genital mutilations. Inguinal areas should be pal-
pated for hernia, gonad, and lymphadenopathy. When anomalies of external genita-
lia are detected, either gynecologic conditions, dermatologic disease or systemic
disease have to be taken into account.
Clinically it is possible to discern two conditions:
• Vulvitis: it is the inflammation of the vulva characterized by hyperemia and other

skin alterations limited to the vulvar region. In most cases, vulvitis are caused by
allergies or simply a reaction to an irritant (33%) [13].
• Vulvovaginitis: it is vulvar inflammation accompanied by vaginal involvement.
Vaginal abnormal discharge is present. Usually it is caused by proliferation of
pathogenic or opportunistic agents [14].
Vulvitis and vulvovaginitis may exhibit different clinical feature:
• Symptoms (with or without signs)

• Vulvar signs (nonspecific or characteristic lesions)
• Vaginal discharge
Symptoms and nonspecific vulvar skin findings such as itching, dysuria, pain,
burning, scratching lesions, mild redness, and edema are signs of irritations and may
be present in vulvovaginitis whether or not caused by infective agents. Nevertheless,
if girl presents with those clinical features, given that only 1/3 of vulvovaginitis can
be attributed to infections and after reviewing the clinical history, clinicians should
consider that “nonspecific vulvovaginitis” is likely. Bacterial infection, which in any
case has to be taken into account, is often indistinguishable by genital examination

and may require further testing to be diagnosed if suspected; vulvovaginal candidia-
sis is rare unless predisposing factors are present.
Itching in childhood may have multiple origins [15, 16]. Vulvar irritation is
often erroneously attributed to “yeast” infection by clinicians even though candida
infection is sporadic in prepubertal child. It has been calculated that up to 75% of
vulvar itching is associated with negative culture and absence of vulvar disease
[17]. In some cases, itching’s characteristic may give a clue to diagnosis. In pres-
ence of vulvar and perianal hitch, especially at night, it is necessary to consider
the diagnosis of pinworms. Most often pinworms associate with no vulvar findings
or low grade of vulvovaginitis; however, vaginal discharge can be present, espe-
cially if superinfection occurs. Touching transparent adhesive tape to the perianal
area for microscopic examination of the eggs is actually the diagnostic technique,
but often is difficult to obtain. Nocturnal pruritus may also be caused by Sarcoptes
scabiei hominis. Spread is by personal contact. In this case, the inspection of the
skin will detect vesicles or pustules in linear distributions, often in interdigital
folds, flexor, and extensor surface of extremities and genital areas. Classic lesions
appear as grey or white lines but most become excoriated with scratching. Diagnosis
is done with microscopic examination of scarped burrows.
Vaginal discharge is the most common reason for referral of a prepubertal girl to
a gynecologist [5]. It has been reported that, among prepubertal girls presenting with
vaginal discharge, vulvovaginitis is responsible for the majority of cases (82%),
whereas suspected sexual abuse, foreign body, labial adhesions, malformations, and
other causes are less common [18]. Whitish mucoid vaginal discharge due to estrogen
effect is normal in infant, and in girls is associated with pubertal onset and frequently
precedes menarche [7, 19]. Abnormal vaginal discharge can be clear, yellow, green,
bloodstained, and may be offensive smelling [5]. If abnormal vaginal discharge is
present, it may be indicated testing the child for bacterial organisms associated with
vulvovaginitis. Specimens for standard culture may be obtained by introducing into
the lower tract of the vagina an urethral swab moistened in saline water. If the hyme-
neal opening is narrow, it is possible to insert a small urethral catheter attached to a
syringe and obtain vaginal secretions or vaginal wash sample. Recently, it has been
recommended to reserve culture for severe or recurrent vulvovaginitis [20]. The pre-
dominant growth of a pathogen in an appropriate culture is considered the primary
diagnostic tool [2]; in contrast, the presence of normal flora or opportunistic agents
does not necessarily imply that it is the cause of infection [21].
The most common infective agent causing vulvovaginitis in prepubertal girls is
Streptococcus pyogenes. This infection is thought to be transmitted from the throat to
the vulva (up to 92% of throat culture are positive) and it is characterized by sudden
onset of seropurulent–hematic vaginal discharge often associated with distinctive “beefy
red” erythema of vulvar and perianal areas (Fig. 1.1); aspecific signs and symptoms of
vulvovaginitis, pharyngitis, scarlet fever, and guttate psoriasis may be associated [7].
Staphylococcus aureus may cause opportunistic skin infections which may
appear as impetiginous, bullous, or suppurative.
In case of suspected sexually transmitted disease, evaluation for Neisseria
Gonorrhoeae and Chlamydia Trachomatis can be obtained sending a urine or vagi-
nal sampling for NAAT (nucleic acid amplification testing). Trichomonas
6 C. Vezzani et al.
Fig. 1.1 Streptococcus

pyogenes vulvovaginitis
vaginalis can be identified in vaginal secretions by wet mount examination, cul-

ture or NAAT. When sexually transmitted diseases are detected and mother to child
transmission can be excluded, sexual abuse should be considered.
Physical examination is usually sufficient to diagnose viral genital infection,
since they show characteristic lesions.
Feces and urine culture may be useful respectively in cases of diarrheal illness
and dysuria.
1.4.1 Vulvar Lesions
As symptoms of vulvovaginitis, vulvar dermatosis, and systemic disease with vulvar

manifestations may often overlap, recovery of specific vulvar lesions may give a clue
to diagnosis. Hence, awareness of vulvar lesion is essential for differential diagnosis.
It has been calculated that, in a series of 130 children presenting with vulvar symp-
toms to a dermatologic clinic, 33% had atopic or irritant dermatitis, 18% had lichen
sclerosus, 17% psoriasis, 15% hemangiomas, less than 20% had infection, and 10%
had streptococcal infection; vulvar manifestations of systemic disease were rare [13].
Systemic diseases with vulvar manifestations include: measles, chickenpox, vari-
cella, scarlet fever, mononucleosis, Stevens-Jonhnson syndrome, Kawasaki disease,
Langherans cell histiocytosis, Crohn disease, Behçet’s syndrome, Staphylococcal
scaled skinsyndrome, Henoch-Schönlein purpura, zinc deficiency [7, 13].
Skin lesions may be differentiated in primary and secondary types (Table 1.1)
[22, 23].
For clinical purpose, it may be helpful to adopt the 2011 ISSVD (International
Society for the Study of Vulvovaginal Disease) Terminology and Classification of
Vulvar Dermatological Disorders as suggested by Lynch [23]. Vulvar diseases may
be clustered into groups with similar clinical presentations. As some skin disease
Table 1.1 Primary and secondary skin lesions

Primary lesions Definitions
Macule Small area (<1.5 cm) of color change; no elevation and no substance on
palpation
Patch Large area (>1.5 cm) of color change; no elevation and no substance on
palpation
Papule Small (<1.5 cm) elevated and palpable lesion
Plaque Large (> 1.5 cm elevated, palpable, and flat topped lesion
Nodule Large (>1.5 cm) papule; often hemispherical or poorly marginated; may
be located on the surface, within, or below the skin; nodules may be
cystic or solid
Vesicle Small (<0.5 cm) fluid filler blister; the fluid is clear (blister: a
compartmentalized, fluid filled elevation of the skin or mucosa)
Bullae A large (>0.5 cm) fluid filled blister; the fluid is clear
Pustula Pus-filled blister; the fluid is white or yellow
Secondary lesions Definitions
Eczema A group of inflammatory diseases that are clinically characterized by the
presence of itchy, poorly marginated red plaques with minor evidence of
microvesiculation and seven or more frequent surface disruption
Lichenification Thickening of the tissue and increase prominence of skin markings.
Scale may or may not be detectable in vulvar lichenification.
Lichenification may be bright-red, dusky-red, white, or skin colored in
appearance
Excoriation Surface disruption (notably excoriation) occurring as a result of the
“itch-scratch” cycle
Erosion A shallow defect in the skin surface; absence of some, or all, of the
epidermis down to the basement membrane; the dermis is intact
Fissure A thin, linear erosion of the skin surface
Ulcer Deeper defect; absence of the epidermis and some, or all, of the dermis
are polymorphic they may be listed in more than one group. For each group, a list
of diseases which may occur in childhood is reported below (adapted from [23]):
1.4.1.1 Skin Colored Lesions

Papules and nodules may be caused by Human Papilloma Virus, Molluscum conta-
giosum, skin tag, epidermal and mucinous cyst, scar, and nevus. If the lesion is
single and appears on the median rafe of perineum the differential diagnosis include
the infantile perianal pyramidal protrusion, which is a peduncolated congenital
protrusion typically located anterior to the anus [7]. Plaques are present in lichen
simplex chronicus and other lichenified disease.
The hallmark of Human Papilloma Virus (HPV) infection is condyloma acu-
minata which may appear as papule or nodule, solitary or multiple. Lesion may
be skin colored, red, white, or dark colored. Acquisition of the virus may occur
by mother during gestation or delivery. Postnatal infection may be acquired
through inoculation from nongenital mucocutaneous lesion or fomite transmis-
sion [24, 25].
Umbilicated and caseous-plug containing papules are typically caused by
Molluscum contagiosum. Lesions may be single or, more often, multiple; skin
8 C. Vezzani et al.
colored, white, red, dark colored. Size of lesions ranges from 1 to 5 mm (giant
lesions up to 1.5 cm are rare, may be present in HIV infection) [26]. Transmission
may occur by casual contact, fomite spread, autoinoculation, and sexual contact.
Treatment options include: watchful waiting (spontaneous resolution may take
month or years), off-label application of imiquimod or tretinoin, curettage, and dia-
termocoagulation [7].
1.4.1.2 Red Patches and Plaques

Clinicians should consider allergic/irritant/atopic dermatitis, eczematous changes
superimposed on other vulvar disorders, candidiasis, psoriasis, lichen simplex
chronicus, lichen planus, hemangioma of infancy, cellulitis, pityriasis rosea, zinc
deficiency, Langherans cell histiocytosis.
Psoriasis is a chronic immune-mediated inflammatory disease which may
involve skin and/or joints [27]. Lesions are red-pink, symmetric, well-demarcated
plaques. Scales are seen at the periphery. Skin lesions affecting the scalp and exten-
sor surfaces of the limbs (elbows and knees) are typical of adulthood, whereas vul-
var and anogenital localization are the most frequent in childhood [26].
Atopic dermatitis is a skin chronic disease with complex pathogenesis (genetic,
immunologic, and environmental factors are involved). Lesions are erythematous
scaly plaques with undefined margins. Lichenifications may compare with time and
scratching. The disease may be indistinguishable from contact dermatitis (Fig. 1.2).
Contact dermatitis (irritant and allergic) may present as acute or subacute/
chronic disease. Acute manifestations may be erythema, edema, and vesicle which
evolve into painful erosions and ulcerations. Subacute and chronic dermatitis may
appear with erythema, lichenification, red plaques, excoriations, and fissures [7].
A particular condition frequently found in pediatric age is irritant diaper der-
matitis. It commonly affects infants with a peak incidence between 9 and 12
months. It appears as perineal erythema, restricted to the area covered by diapers but
Fig. 1.2 Atopic dermatitis

usually spares inguinal areas [28, 29]. Macerations, erosions, and ulcerations may
be associated. It is caused by overhydration of the skin, maceration, prolonged con-
tact with urine and faces, retained diaper soap and is a prototypical example of
irritant contact dermatitis [30]. Moreover, the onset of secondary infection caused
by Candida albicans or bacteria such as Bacillus faecalis, Proteus, Pseudomonas,
Staphylococcus, and Streptococcus is frequent. Candidal diaper dermatitis is a
superficial infection of skin, involving perineal skin, buttock, lower abdomen, ingui-
nal areas, characterized by beefy red erythema often associated to maceration, ero-
sions, and ulcerations [7].
Piritiasis rosea is a papulosquamous eruption usually presenting on the trunk
along the skin tension lines. In children lesions may involve the pubic, inguinal and
axillary areas. Viral etiology is suspected [7, 14].
Hemangioma of infancy is a benign vascular neoplasm, the most common
tumor of infancy. Usually not evident at birth, it grows rapidly during the first year
of life, appearing as a flat or raised lesion, red or blue colored. Sometimes ulcerate
and lead to infection. It may be associated with urogenital an anorectal
malformations.
Zinc deficiency is a rare inherited (acrodermatitis enteropathica) or aquired dis-
order characterized by the inability of absorb sufficient zinc from diet. Skin findings
include red, erosive plaques that may contain vesicles and pustules, simmetrically
distributed in the perioral, acral, and perineal areas [7, 31].
1.4.1.3 Red Papules and Nodules

Red papules and nodules may be caused by folliculitis, HPV, Molluscum contagiosum,
hidradenitis suppurativa, urethral prolapse, hemangioma of infancy, pityriasis rosea.
1.4.1.4 White Lesions

The most frequent white lesion in childhood is caused by lichen sclerosus. Other
diseases are vitiligo, Molluscum contagiosum, and HPV.
Lichen sclerosus is a chronic autoimmune skin disease, in adulthood often asso-
ciated with other autoimmune disease. Genetic and hormonal factors are involved
also [12]. It affects all areas of the body in both sexes and all ages, but in children
extragenital lesions are rare and average age of onset is 5 years [14, 31]. The key
feature of lichen is a well-demarcated white plaque in a figure of eight distribution
surrounding the vulva and perineal areas. Petechiae and ecchymoses may be present
(Fig. 1.3). Skin is usually wrinkled (Fig. 1.4). The vulvar rash is extremely pruritic,
and irritation, pain, dysuria, bleeding, constipation, and dyschezia may associate. In
contrast, many cases are asymptomatic. Generally the diagnosis is made by clinical
examination, therefore biopsy is not necessary. Symptoms usually improve at men-
arche. Many patients have relapses and remits over time. It has been reported that
lichen sclerosus may increase the risk of vulvar squamous cell carcinoma. Treatment
of choice, whose objective is to relief symptoms and avoid scars, is topical cortico-
steroids (clobetasol propionate 0.05% or betamethasone valerate 0.05%). Off-label
treatment with topic tacrolimus or pimecrolimus may be an option as second-line
treatment [20].
10 C. Vezzani et al.
Fig. 1.3 Lichen sclerosus
Fig. 1.4 Lichen sclerosus
Lichen simplex chronicus may be present in all ages and may be distinguished
in primary (arising from normal appearing skin) or secondary (superimposed on
some other underlying dermatological disorders). It is characterized by the presence
of itch-scratch cycle and clinically by a palpable thickening of the tissue and
increased prominence of skin markings. Color of lesions may vary from white to
skin colored or red [23].
Vitiligo is an aquired, autoimmune disorder due to an absence of epidermal
melanocytes. Lesions are asymptomatic, sharply demarcated patches with complete
loss of pigment, often involving periorificial areas in a symmetric manner [7].
1.4.1.5 Dark-Colored Lesions

Acanthosis nigricans, nevi, lentigines, HPV, and seborrheic keratosis may appear as
dark-colored lesions.
Acanthosis nigricans is characterized by thickening and hyperpigmentation of
the skin. Symptoms are absent. It usually involves the skin of axillae, posterior
neck, groins, bell line, dorsal surface of fingers, mouth and around areolas. It is
considered as markers of insulin resistance.
1.4.1.6 Blisters
If blister lesions (vesicles and bullae) are present, clinician should consider HSV,
varicella, eczema but also autoimmune disease such as childhood vulvar pemphi-
goid and chronic bullous disease of childhood should be kept in mind.
1.4.1.7 Erosions and Ulcers

Genital erosions and ulcers may be caused by infections, inflammatory diseases,
malignancy medications, and trauma.
Infectious agents typically associated with ulcers are Herpes simplex viruses
(Fig. 1.5), Haemophilus ducreyi (chancroid), Treponema pallidum (syphilis),
Fig. 1.5 Herpes Simplex

Virus
Epstein Barr virus (mononucleosis), Cytomegalovirus, Influenzae viruses, and

streptococci [32, 33].
Ulcers may be caused by inflammatory disease such as Behçet’s syndrome and
Crohn disease, childhood vulvar pemphigoid, hidradenitis suppurativa, Jacquet ero-
sive dermatitis, pyoderma gangrenosus, and Reiter syndrome.
Behçet’s syndrome is a chronic, relapsing systemic vasculitis of unknown etiol-
ogy. It is rare in childhood but may be considered when child presents with recurrent,
painful oral and/or genital ulcers that may be single or multiple, shallow or deep,
round to oval in shape, and have a yellowish necrotic base [34, 35]. Diagnosis
includes presence of oral aphthous ulcers recurring at least three times a year, plus at
least two of the following: recurrent genital ulcers, uveitis or retinal vasculitis, skin
involvement such as erythema nodosum, or a positive pathergy test.
Crohn disease is a chronic inflammatory bowel disease characterized by trans-
mural skip lesions that can occur anywhere in the gastrointestinal tract from the
mouth to the anus. In addition to gastrointestinal tract lesions several reports have
described cutaneous and genital manifestations, defined as “metastatic Chron.”
Vulvar Crohn disease may be the first clinical sign of the disease. Lesions typically
begin with painful vulvar asymmetric edema or mass, erythema and progressive
ulceration. A biopsy of the lesion is necessary to a definitive diagnosis [36].
Lipschutz ulcers or vulvar aphthosis refers to acute genital ulcers associated
with viral or unknown etiology. Usually it is preceded by febrile illness and it may
be associated to mouth ulcers. Diagnosis is made on the basis of clinical history and
exclusion of other diseases (Herpes viruses and Behçet’s syndrome) [7].
Depending on the level of suspicion, consultation with a specialist (dermatology,
gastroenterology, ophthalmology, or rheumatology) may be necessary to exclude a
specific diagnosis. The biopsy is necessary in some cases and serology may be help-
ful. If sexually transmitted disease is diagnosed, sexual abuse should be excluded in
absence of evidence of different transmission.
1.4.1.8 Edema
Mild edema may occur with any inflammatory disease. Diffuse genital edema may
be present in Crohn disease or post staphylococcal and streptococcal cellulitis.
1.4.2 Labial Adhesions
Although not included in the classification described above, agglutination of labia

minora represents a vulvar condition affecting up to 2–5% of young girl, usually
among 6 months and 7 years age [14]. Initial small posterior adhesions may prog-
ress to near-total fusion. Possible explanation for adhesions is hypoestrogenism
combined with tissue hyper-reactivity and vulvar flogosis. Symptoms, when pres-
ent, include postvoid leakage of urine, urinary infections, and nonspecific vulvo-
vaginal complaints. The diagnosis is made by visual inspection of the vulva
(Fig. 1.6). Treatment is not always necessary, especially when symptoms are absent,
since spontaneous resolution occurs in up to 80% of cases. Topical medication
Fig. 1.6 Labial adhesions
consists in estrogen containing cream twice daily for 3 weeks and then once a day
for 2–4 weeks [37]; in alternative, betamethasone cream 0.05% can be applied
twice daily for 4–6 weeks [38]. In cases of symptomatic adhesions or urinary
obstruction, application of topical anesthetic followed by manual separation can be
performed: Q-tip is inserted behind the labia minora and slides gently along the
adhesions [38]. Risk or recurrence is elevated (40%) but can be reduced by improv-
ing perineal hygiene and with use of ointment [20].
1.5 Management of Vulvovaginitis
Most cases of nonspecific vulvovaginitis resolve by following hygiene education

and lifestyle recommendations:
–– Wiping front to back after using the toilet

–– Void with legs open
–– Use plain white toilet paper
–– Wash hands frequently
–– Use and frequent changes of cotton underpants
–– Avoidance of tight induments
–– Avoidance of harsh soap and bubble baths
–– Vulva and perianal area should be washed with water or mild unscented soap
Table 1.2 Treatment of specific vulvovaginal infections

Etiology Drugs Dosage
Pinworm Mebendazole Oral, 100 mg or 5 mL suspension once,
repeated in 2 weeks
Pyrantel pamoate Oral, 11 mg/kg once, repeated in 2 weeks
Albendazole Oral, 400 mg once, repeated in 2 weeks
Sarcoptes scabiei Permethrin 5% cream applied from head to toe, at
least 8 h overnight, repeated 7 days later
Streptococcus pyogenes Amoxicillin Oral, 20 mg/kg every 12 h, for 5–10 days
(21 days for perianal infection)
Haemophilus influenzae Amoxicillin Oral, 20 mg/kg every 12 h, for 5–10 days
Candida albicans Clotrimazole Topical, 6 days
Miconazole
Candida glabrata Isoconazolo Topical, 10 days
Sertaconazole
Boric acid
Yersinia and Shigella Trimethoprim- Oral 5 mg/kg every 12 h for 5–10 days
sulfamethoxazole
Dei and Bruni [14], Zuckerman and Romano [40] and Emans and Laufer [7]
–– Vulva and perianal area should be let dried avoiding rubbing
If symptoms are mild, using an emollient cream or ointment may be useful. In

severely symptomatic patient, a 1–2.5% hydrocortisone cream can be used once or
twice a day for 2 weeks [39].
The need for pharmacologic treatment in cases of positive culture for normal
flora/opportunistic pathogens is questionable, as the presence of a microorganism
does not necessarily imply that it is the cause of infection [21]. Furthermore, the
extensive use of antibiotics is associated to emergence of multidrug resistant bacte-
ria. The first step of treatment should be the use of oral probiotics, sitz bath, and
local application of antiseptic ointment or solution (benzydamine/clorexidine).
Empirical administration of topic antimicrobials (gentamicin/fusidic acid/metroni-
dazole + nifuratel/netilmicin + chloride benzalkonium/cyclopiroxilamine) may be
acceptable when aspecific superinfection is suspected. Severity of symptoms and
patient’s state of health may indicate need for specific systemic treatment [2, 40].
Patients with specific infection should be treated as follows (Table 1.2):
Pinworm should be treated in cases of suspected or confirmed infection. Family
members should be treated if symptomatic. Washing of underwear and bedding is
recommended.
Treatment for Sarcoptes scabiei should be applied by patients and closed con-
tacts [31].
Impetiginous lesions of buttocks or vulvar skins, caused by Staphylococcus
aureus, can be treated with topical mupirocin 2% applied three times daily. If sys-
temic antibiotic is necessary, susceptibility test should be performed.
1.6 Recurrent Vulvovaginitis
If vulvovaginitis persist despite lifestyle changes and first-line treatment, it is impor-

tant to overview the diagnosis, evaluate urinary and intestinal function and consider
the possibility of multidrug resistant bacteria.
Foreign body (rolled toilet paper is the most frequent) is responsible for up to
20% of recurrent vulvovaginal discharge and may be associated to hematic dis-
charge. Urinary dysfunctions (especially hyperactive bladder, dysfunctional urina-
tion, urinary vaginal reflux) and chronic constipation also may play a role in favoring
recurrences of infections [14]. Relapses of vulvovaginitis caused by Streptococcus
pyogenes, which occur in up to a third of treated individuals, may be associated with
pharyngeal carriage [5].
Moreover, other causes have to be excluded: polyps, tumor, sexual abuse, psy-
chosomatic vaginal complaints, draining pelvic abscess, prolapsed urethra, allergy
to pollen, ectopic ureter in vagina, vaginal malformation with stagnation of mucus
and pus in obstructed hemivagina, rectovaginal fistulae due to genital mutilation or
Crohn disease. If inspection of upper vaginal canal or cervix is needed, vaginoscopy
under general anesthetic should be performed. Allergologic consultation may be
useful in patients with allergic diathesis or familiarity for allergies [14].
Single course of estrogen containing cream applied for 1–2 weeks can be used in
selected cases to thicken the epithelium and facilitate healing (Emans and Laufer
2012; [14, 39]). Even in absence of specific studies many clinicians have found that
10–14 days of empirical treatment with topical gentamicin/mupirocin/metronida-
zole/cyclopiroxilamine or systemic (amoxicillin/clavulonate or cephalosporin) anti-
biotics for 10–14 days [7] may lead to resolution of recurrences. In cases of recurrent
candida infections, secondary to prolonged antibiotic treatment or immune defi-
ciency, oral fluconazole 3 mg/kg once daily is recommended [14].
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Delayed Puberty
2
Metella Dei and Francesca Pampaloni
Abbreviations
AMH Anti-Mullerian hormone

CD Coeliac disease
CDGP Constitutional delay of growth and puberty
CSF Cerebrospinal fluid
DP Delayed puberty
FHH Functional hypogonadotropic hypogonadism
FSH Follicle stimulating hormone
GD Growth hormone deficiency
Gh Growth hormone
GhRH Growth hormone releasing hormone
GnRH Gonadotropin hormone releasing hormone
HH Hypogonadotropic hypogonadism
IGD Isolated Gh deficiency
IGF-1 Insulin growth factor-1
KS Kallmann syndrome
LH Luteotropic hormone
PRL Prolactin
SSRI Selective serotonin reuptake inhibitors
TIDA Tuberoinfundibular dopamineagonists
M. Dei, M.D. (*)

Italian Society of Pediatric and Adolescent Gynecology, Florence, Italy
F. Pampaloni, M.D.
Pediatric and Adolescent Gynecology Unit, Careggi Hospital, Florence, Italy

20 M. Dei and F. Pampaloni
2.1 Definition and Pathogenesis
We define a delayed puberty (DP), warranting a diagnostic evaluation, as:
1 . Lack of breast development by age 13

2. Lack of menarche by age 15 in the presence of secondary sexual characteristics
3. Lack of menarche 4 years after the beginning of breast development (thelarche)
These criteria, based on two standard deviations from normal range of pubertal
timing of European Caucasian girls, can be, in the clinical practice, extended also to
African girls (whose pubertal development starts earlier) and to Asian girls. The
presence of clues of specific conditions (malnutrition, poor growth, reduced sense
of smell, cyclic pelvic pain, androgen excess) can suggest the need of an earlier
evaluation.
As the first menstrual bleeding is the endpoint of the maturation of genital organs
and of various endocrine systems, the failure to undergo menarche could be second-
ary to:
–– Genital malformations as genital tract outflow obstructions or Mullerian Agenesis

(or Rokitansky, Kuster, Hauser, Mayer syndrome) described in Chap. 3
–– Primary gonadal failure, present in more than 25% of girls with lack of physio-
logical sexual development (see Chap. 4)
–– Secondary gonadal failure due to antineoplastic therapy or, rarely, to autoim-
mune processes
–– Deficiency of gonadotropin production, the specific topic of this chapter
Impaired gonadotropin release is linked to a wide variety of underlying condi-

tions leading to delayed or absent puberty (Table 2.1). Recent genetic studies have
demonstrated a significant overlap between CDGP and GD and among different
forms of HH, so our classification will probably change in the next years.
Considering the relative frequencies of the various etiologies, we estimate that
more than 30% of female subjects with DP have a constitutional delay; functional
hypogonadisms now account for almost 40% (for the increasing incidence of eating
disorders in very young girls). The remaining subjects are affected by other causes.
2.1.1 Hypogonadotropic Hypogonadism
HH includes various congenital deficiencies of GnRH production, not involving

other pituitary tropins. In Table 2.2, the well-defined syndromes in female subjects
are summarized.
The Kallmann syndrome (KS) is the association of isolated hypogonadotropic
hypogonadism (HH) and reduced or absent smell sense: the association provides
evidence that the dysfunction of GnRH neurons activity is related to their impaired
migration during intrauterine life from olfactory area to hypothalamus. The preva-
lence of Kallmann syndrome is rare (1:50,000 in females) and related to mutations
2 Delayed Puberty 21
Table 2.1 Pathogenesis of hypogonadism

Hypogonadotropic hypogonadism Kallmann syndrome
(HH) Isolated gonadotropin deficiency
Charge syndrome
Leptin deficiency
Organic CNS pathologies Congenital hypopituitarism (complete or partial)
Congenital hypogonadotropic hypogonadism
Midline cerebral and cranial malformations
Empty sella syndrome
Iron overload secondary to hemoglobinopathies,
aplastic anemias, juvenile hereditary hemochromatosis
Sarcoidosis, granulomatous infections (tuberculosis),
Langerhans cell histiocytosis
Autoimmune hypophysitis
Rathke’s pouch cysts
Arachnoid, dermoid, or epidermoid cysts
Obstructive hydrocephalus
CNS tumors
Repercussions of trauma, surgery, vasculopathies
Long-term effects of antineoplastic treatments
Hyperprolactinemia Prolactinoma or other pituitary adenomas
Pituitary stalk lesions
Drugs affecting prolactin secretion
Gh deficiency (GD) Isolated
Syndromic (Noonan syndrome, Prader–Willi syndrome)
Constitutional delay of growth and
puberty (CDGP)
Functional hypogonadotropic Eating disorders
hypogonadisms (FHH) Strenuous physical activity
Coeliac disease (CD)
Chronic diseases
Endocrinopathies (Cushing syndrome, 21α hydroxylase
deficiency, hypothyroidism)
Long-term corticosteroid treatment
Endocrine disrupters
Table 2.2 Hypogonadotropic hypogonadism

Associated defects Known involved genes
Kallmann syndrome Hypo-anosmia; infrequently cleft ANOS1, FGFR1, FGF8, PROK2,
palate, synkinesis, unilateral PROKR2, WDR11, CHD7, NELF,
kidney agenesis, hearing defects HS6ST1, SOX10, SEMA3A, FEZf1
Isolated GnRHR, GnRH1, FSHb, FGFR1,
hypogonadism GPR54/KISS1R, KISS1, TAC3/
TACR3, NR5A1, PIN1, NNKB,
NKR3 (FGFR1, FGF8, PROKR2,
CHD7, WDR11)
Charge syndrome Coloboma, cardiac malformations, CHD7
atresia choanae, external genital
hypoplasia, ear anomalies, growth
anomalies
Leptin deficiency Obesity, immunological deficiency LEP, LEPR
of different genes; it is mainly sporadic; sometimes familiar transmissions X linked

or autosomic recessive or autosomic dominant have been documented. Consequently,
the phenotype is also variable concerning olfactory ability, secondary sex character-
istics development and associated defects. The possibility of a late recovery of
hypogonadism has been described in few cases [1].
For the diagnostic workup, it should be kept in mind that the self-evaluation of
smell is generally unreliable except in subjects who admit anosmia; so it should be
investigated with a selection of essential oils or scented papers or with specific stan-
dard kits. In KS the growth is linear, without spurts, exceeding the average for
chronological age and inappropriate for bone age, with a prevalent increase of arms
and legs, because the physiological pubertal shift between legs and trunk increase
doesn’t take place.
Isolated hypogonadism includes various diseases with different stages of puber-
tal delay without other functional (even if small impairment in olfactory ability is
sometimes present) or somatic defects and with normal brain imaging. The underly-
ing genetic mutations are various and overlapping with alterations in genes involved
also in KS [2].
The CHARGE syndrome (Coloboma, Heart defects, Choanal atresia, Retarded
growth and development, Genital abnormalities, Ear anomalies) is a rare associa-
tion, mainly sporadic of several anomalies related in more than 60% of cases to
CHD7 gene mutation. The hypogonadism may result from the same migration
defects of KD and is associated with growth, coloboma of iris and sometimes of
retina, choanal atresia, internal and external ear abnormalities, and heart malforma-
tions. Cranial nerve defects with problems with breathing and feeding, orofacial
clefts, defective sense of smell, vestibular abnormalities, hearing loss, and genital
hypoplasia are also common.
The association between hypogonadotropic hypogonadism and leptin deficiency
or leptin receptor anomalies entails, in typical forms, obesity and a higher preva-
lence of infections for an associated T cell functional anomaly; actually leptin muta-
tions have been described even in subjects mildly overweight or normal and with
normal immunologic defenses.
2.1.2 Organic CNS Pathologies
Gonadotropin deficiency can be present in congenital diseases involving the pro-

duction of other pituitary hormones, linked to mutations of genes encoding tran-
scription factors involved in the ontogenesis of pituitary gland or of
hypothalamus-pituitary axis. The diagnosis is usually made during infancy and a
definite cytogenetic testing is very important in order to plan the follow-up needed
to prevent clinical outcomes related to late onset deficiencies [3]. Rare congenital
midline cerebral and cranial malformations, i.e., septo-optic dysplasia or absence of
septum pellucidum with optic hypoplasia, are associated with endocrine pituitary
dysfunction. More frequent is the empty sella syndrome, characterized by cerebro-
spinal fluid filling the sella; as a result, the pituitary gland is often compressed and
flattened. Empty sella may occur as a primary disorder because of an herniation of

the arachnoid through a defect in the diaphragma sellae or as a secondary disorder
due to damage to the pituitary itself, for instance as long-term consequence of sur-
gery, radiation therapy, or of autoimmune hypophysitis. In most cases empty sella is
asymptomatic; in adolescents could be associated with endocrine abnormalities: Gh
and gonadotropin deficiency or hyperprolactinemia.
The pituitary gland is characterized by a very high blood flow (0.8 mL/g/min)
and therefore is very exposed to overload phenomena especially iron overload. A
pituitary injury may arise, in spite of the progress of chelation therapy, as a conse-
quence of iron deposition in reticuloendothelial cells in subjects with hemoglobin-
opathies (thalassemia, hemolytic or aplastic anemias), who need transfusion therapy
(transfusional hemosiderosis). The iron overload increases gradually reducing the
pituitary volume and function; chronic hypoxia and ineffective erythropoiesis con-
tribute to the endocrine impairment often involving also the growth hormone pro-
duction. A significant iron overload in pubertal age is rare in subjects affected by
hereditary idiopathic hemochromatosis [4]: in this disease, the deposition is mainly
at parenchymal level but very slow and endocrine repercussions appear in older age.
The history of relatives affected by the disease, the tiredness, the elevation of liver
enzymes and ferritin, and the transferrin saturation of more than 45% address to a
more detailed study including genotype.
Neurosarcoidosis and Langerhans cell histiocytosis are uncommon in adoles-
cence; pituitary tuberculous infiltration has been described in adolescents living in
other countries. Autoimmune hypophysitis is an inflammation of the pituitary gland
due to the attack of T lymphocytes against secreting pituitary cells, sometimes sec-
ondary to systemic diseases, infections, or immunomodulating treatments. It occurs
more commonly during and shortly after pregnancy, but it is described also in ado-
lescence. Autoimmune damage of the pituitary gland results in the deficiency of
various tropins and often diabetes insipidus. Autoantibodies against pituitary (APA),
sometimes against hypothalamus (AHA) and thyroid gland, can be detectable.
Specific mutation of CTLA-4 gene can predispose to this disease.
The Rathke’s pouch is embryologically an ectodermic evagination at the roof of
the developing mouth that gives rise to the anterior pituitary; its posterior wall
remains as intermediate lobe of the gland. Fluid-filled cysts can arise from the
expansion of remnants of this formation. They are generally asymptomatic, but
sometimes exert compression on adjacent pituitary tissue and distortion of the pitu-
itary stalk. Arachnoid cysts are probably derived by congenital splitting of the
arachnoid layer with accumulation of CSF within this potential space and usually
located in the middle cranial fossa. The majority of arachnoid cysts are asymptom-
atic, but sometimes their gradual enlargement produces a mass effect resulting in
either direct neurological or endocrine dysfunction or distortion of normal CSF
pathways.
A chronic obstructive hydrocephalus may be derived from a congenital stenosis
at or below the level of the aqueduct of Sylvius, connecting the third to fourth ven-
tricle (often on genetic basis), or from compression gradually exerted by a colloid
or an arachnoid cyst on the third ventricle located on the diencephalon of the
forebrain between the right and left thalamus. It may cause a distension of the peri-
ventricular or medial basal hypothalamus disrupting the physiological release of
GnRH; sometimes hypothyroidism and anomalies of Gh secretion are associated. In
congenital aqueduct stenosis, the presence of symptoms of increased intracranial
pressure (headache, nausea, vomiting, papilledema) is very rare and the situation is
mainly asymptomatic.
Considering the tumors affecting the hypothalamic-pituitary region, craniopha-
ryngioma is a dysontogenic lesion arising, near the pituitary stalk, from the epithe-
lial nests of craniopharyngeal duct or of Rathke’s pouch. The prevalence is about
1:50,000 subjects. It is a capsulated tumor, with slow evolution but with a tendency
to invade surrounding structures and to recur after resection. At the beginning of its
growth symptoms are uncommon, so the diagnosis is often delayed when the pres-
sure on the optic tract or on the pituitary gland causes impaired vision, growth and
pubertal delay, obesity, insipid diabetes or when an intracranial hypertension has
been established. Vomiting in the morning and pathological rate of growth are gen-
erally the early manifestations of the disease [5]. Pituicytoma arising from pituitary
parenchyma or germinoma and teratoma growing from germ cells inclusions can
also involve the sella region as well as neoplastic lesions coming from adjacent
structures.
Traumatic brain injuries can lead to acute endocrine changes but also both tem-
porary and permanent alterations of pituitary function in the long term: the most
common are Gh deficiency and alterations of puberty. We estimate that 3 months
after the trauma about 35% of children and adolescents display pituitary secretion
abnormalities and 30% after 12 months. A spontaneous recovery is possible, but
permanent deficiencies have been documented [6]. A deficiency in gonadotropin
secretion can be the long-term effect of treatments (mainly radiation) of leukemia
and brain tumors even if therapeutic procedures with less impact on endocrine func-
tion are increasingly under study.
2.1.3 Hyperprolactinemia
An hyperprolactinemia is infrequently a cause of delayed puberty. A prolactin

excess can be related to a PRL secreting (or Gh secreting) adenoma or to other
intracranial pathologies (chordoma or other neoplasia) causing a pituitary stalk
interruption or dislocation (pseudo-prolactinoma). The compression on the stalk
may impair the function of TIDA (TuberoInfundibular DopAmine) neurons that
physiologically inhibit the secretory activity of PRL cells. An hyperprolactinemia
can also be associated to hormone deficiencies secondary to pathologies damaging
the hypothalamus-pituitary region, as already mentioned. A prolactin excess related
to primary hypothyroidism, linked to TSH secreting cells hyperplasia, has also been
described. Increased prolactin concentrations as a consequence of drug intake, espe-
cially psychiatric drugs (Table 2.3), are more frequent; so a pharmacological anam-
nesis is always mandatory.
Table 2.3 Hyperprolactinemic drugs

Antipsychotic Haloperidol, Chlorpromazine,
Thioridazine, Thiothixene
Risperidone, Paliperidone, Sulpiride,
Amisulpride, Molindone, Zotepine
(Olanzapine, Clozapine)
Antidepressants Tricyclic Amitriptylin, Desipramine,
Clomipramine, Amoxapine
SSRI Sertraline, Fluoxetine,
Paroxetine
Prokinetics Metoclopramide,
Domperidone
Opiates Morphine
H2 antagonists Cimetidine, Ranitidine
Others Physostigmine, antineoplastic
drugs
In subjects with prolactinoma, the history and the symptomatology can be insig-
nificant: the linear growth is generally normal, neurological symptoms mostly
absent, and galactorrhea is rare in this age group.
2.1.4 Gh Deficiency
Isolated Gh deficiency (IGD) can be acquired (as result of trauma, infection, radia-
tion therapy, or tumor growth), or congenital on genetic basis: the genes coding for
Gh (Gh1), its receptor (GhRHR) and Ghrelin receptor (GhSR) are the most com-
monly involved; less often mutations of transcription factors active in pituitary
development are involved. However, known mutations explain only a small per-
centage of clinical cases (several GD are diagnosed as idiopathic); moreover, geno-
type–phenotype correlation is not univocal and is variable over time. Subjects with
GD may present with insufficient growth velocity and delayed growth spurt, con-
sidering their chronological age. Slow tooth eruption and poor nail growth can be
present in the history. In subjects with previous diagnosis of IGD and under treat-
ment the pubertal timing is generally normal.
Noonan syndrome is a heterogeneous genetic disorder, typically evident at birth,
characterized by a wide spectrum of physical features: abnormalities of head and
face, skeletal and vascular malformations, heart defects, delay of growth and
puberty. The incidence is 1:1500 subjects. The Prader–Willi syndrome is a genetic
disorder affecting 1:30,000 births due to the missed expression of genes imprinted
on the chromosome 15. The girls affected display growth and sexual development
delay and obesity secondary to hyperphagia. The hypogonadism can be related to a
central defect with late menarche (about 20 years); a primary gonadal defect can
also be present.
2.1.5 Constitutional Delay of Growth and Puberty
In more than 60% of cases a familiarity can be demonstrated, with an autosomic

dominant transmission. Genetic studies highlighted mutations of GnRH Receptor,
GhSR, an endogenous Ghrelin ligand, of genes involved also in IGD, and of genes
significant in the pathogenesis of HH. Subjects affected by CDGP have an overall
delay in the appearance of sex characteristics, the growth spurt, and the develop-
ment of internal genitalia of, on average, 2 years and a half, with normal nutritional
status. The time span between the thelarche and the beginning of growth spurt is
generally reduced; but height velocity is lower than in normal subjects. The current
height is in agreement with bone age more than with chronological age.
2.1.6 F
unctional or Secondary Hypogonadotropic
Hypogonadism
Eating disorders are becoming more frequent in preadolescent, considering the

trend to a precocious onset of these unhealthy behaviors. Restrictive food intake or
selective eating can induce an energy deficiency impairing the normal timing of
GnRH neurons activation. Dissatisfaction with their own look and concern about
weight can be evident or not. Sometimes, a history of eating disturbances in infancy
or of precocious traumatic events is present. Psychopathological traits (anxiety or
depression) in the relatives are frequent. A reduced nutritional intake induces a
decrease of linear growth and a slowing of pubertal maturation, evident at breast
level. Considering body composition a reduced fat deposition and a slow bone mass
apposition occur, with a slight increment in fracture risk. The symptoms are related
to the mechanisms of adjustment to reduced energy intake (see Chap. 8) and are
directly related to the seriousness of the clinical situation. The young athletes under-
taking strenuous training programs in peripubertal age may undergo to a period of
reduced energy availability for the needs of anabolic processes related to pubertal
development, with resulting repercussion on hypothalamus-pituitary-ovarian axis
activation. This effect is particularly evident if restrictive eating is associated, some-
times following the esthetic appeal required for certain physical activities, as in
gymnasts, dancers, skaters, and wrestlers. From a clinical point of view the prepu-
bertal phase is prolonged, as well as the first stages of puberty development, the
growth potential is attenuated, and the relative proportions of lean and fat body mass
are modified.
Undiagnosed or untreated coeliac disease (CD) is often associated with pubertal
maturation delay and sometimes with growth impairment considering the genetic
target. The pathogenesis is multifactorial: in addition to nutrients deficiency and
body composition alterations, the involvement of autoimmune processes is now
under study. The estimated prevalence of this condition is 1% of population. The
hallmark of CD is an immune-mediated enteropathy elicited by gluten in genetic
susceptible individuals, but gastrointestinal symptoms can be absent; sideropenic
Table 2.4 Chronic diseases Chronic liver diseases, alpha1-antitrypsin deficiency,

associated with pubertal congenital biliary tract atresia
delay Congenital heart malformations
Chronic inflammatory bowel diseases
Cystic fibrosis
Epilepsy, cerebral palsy
Hemoglobinopathies (thalassemia, sickle cell disease),
Fanconi anemia
HIV infection
Insulin-dependent diabetes
Nephrotic syndrome, renal insufficiency
Juvenile idiopathic arthritis
Juvenile LES
Severe chronic asthma
anemia, raised liver enzymes, and autoimmune thyroiditis may be found. The
research and the identification of CD in adolescents with faltering growth and
delayed puberty are supported by evidence criteria [7].
We estimate that a chronic disease (Table 2.4) affects more than 10% of young
people: in a majority of cases the energy deficiency, the metabolic impairment, the
changes in body composition, the chronic hypoxia, the opportunistic infections,
sometimes the treatments impact on pubertal development slowing it down and
delaying menarche. The level of involvement depends on the type of disease, the
age of onset, its duration and severity, and on the individual response to therapy
[8]. Considering 25% begins under 18 years of age: Crohn disease especially is
associated with growth and puberty delay. In adolescents suffering from insulin-
dependent diabetes and following intensive insulin therapy in agreement with cur-
rent guidelines, the improved glycemic entails minimal impact on timing of
menarche.
Undiagnosed or untreated endocrine diseases can condition pubertal maturation:
–– Hypothyroidism implicates reduced linear growth with higher trunk develop-

ment related to legs and delay in facial bones modifications.
–– Cushing syndrome is very rare in prepuberty and can induce growth delay, trend
to overweight, skin signs of hypercortisolism (striae, acne, hair growth excess);
an episodic cortisol hypersecretion has been described, more difficult to
identify.
–– The glucocorticoid treatment of congenital adrenal hyperplasia can have an
impact on growth and pubertal maturation.
Similar effects can be evident in subjects under extended treatment with gluco-
corticoids for juvenile LES, idiopathic arthritis, and asthma.
Finally, a mention of the possibility of exposure to endocrine disrupters: lead,
dioxins, and polychlorinated dibenzodioxins have been pointed out as possible
causes of pubertal delay [9].
2.2 Diagnostic Workup
The diagnostic evaluation of a patient with pubertal delay is easier if history taking,
physical examination, and laboratory tests are performed bearing in mind the pos-
sible pathogenic spectrum, in order to orient the tests required. So the diagnostic
workup here proposed is illustrative and does not include an in-depth analysis of all
the diseases underlying a secondary functional hypogonadism. Moreover, few dif-
ferential diagnoses usually require a follow-up. In Table 2.5, the first-level diagnos-
tic approach is synthetized.
Sitting height reflects the proportion of girl’s height that is attributed to the head
and the trunk, in relation to legs and is a useful measurement to detect conditions
that affect growth in a disproportional manner. In HH, legs growth is typically
reduced (and SH/TH ratio is less than 50%) while in growth hormone or thyroid
hormones deficiencies it is reduced and SH/TH ratio results increased.
Pelvic ultrasonography, in addition to excluding uterovaginal malformations,
offers a first evaluation of ovarian echostructure and biological appraisal of estro-
genization. The study of uterine length and/or volume and the ratio of anteroposte-
rior diameters of corpus and cervix are well-known criteria of staging of pubertal
maturation. In many cases of functional hypogonadism, pelvic US shows a uterus of
normal morphology but reduced volume and ovaries with microfollicles similar to
physiological prepubertal period. Pelvic US is also an easy method of follow-up if
a CDGP or secondary hypogonadism is suspected.
The bone age, evaluated on a single X-ray of left hand and wrist, is a measure related
to pubertal maturation more than to chronological age; for this reason in the majority of
conditions linked to pubertal delay it results also delayed [10]. In subjects with CDGP
and GD bone age is usually coherent with the mean age corresponding to current height;
this coherence is not present in girls suffering from HH who display delayed bone age
and increased linear growth considering chronological age. In chronic diseases, bone
age is delayed but in agreement with Tanner stage and internal genitalia US develop-
ment. In functional hypogonadotropic hypogonadism, secondary to energy deficiency,
the deviation between bone and chronological age is probably the most significant.
Table 2.5 First-level diagnostic approach

Clinical history Familiar: pubertal delay, shortness, autoimmune diseases
Personal: onset of pubertal signs, physical activity, eating habits, headache,
visual impairment, gastrointestinal problems, pelvic pain known pathologies,
previous or current drugs used, surgery, head trauma
Physical exam BMI, Tanner stages, eventual dysmorphisms, smelling ability, external
genitalia inspection, neurological signs, eventually fundus examination
Auxology Weight (W), height (H), sitting height (SH) and SH/TH ratio, growth chart,
target height (TH)
Imaging Pelvic US scan, bone age
Laboratory FSH, LH, PRL, TSH, FT4, IGF-1 if growth impairment or suspected low
energy availability
Blood tests suggested by history and physical exam
Concerning endocrine evaluation, the increase in FSH level is diagnostic of

gonadal failure (see Chap. 4); in central deficiency gonadotropin concentrations,
especially of LH, are in the lower range, but current assays are not so accurate in the
lower detection limits. So a basal plasma determination is generally unable to dif-
ferentiate between organic deficiency, constitutional delay, and functional impair-
ment. PRL sampling should be performed in the morning but not just after the
awakening, in order to avoid misleading increases related to the circadian rhythm of
the hormone [11]. It is advised to repeat the assay in case of high levels, together
with thyroid hormones and IGF-1 to exclude the involvement of other tropins. If it
is available, Polyethylene Glycol (PEG) precipitation should be tested in order to
screen the presence of macroprolactinemia, large molecular masses of PRL together
with IgG and anti-PRL autoantibodies, with poor biological activity. This phenom-
enon is however rare in young ages. The 17β estradiol dosage is generally not so
significant because it is usually performed with methodology with poor sensitivity
in the lower range: the use of integrated measurement (i.e., early morning urinary
determination) and of different methodology (liquid chromatography and gas spec-
trometry) could add more information. The usefulness of follicular activity markers
(AMH, Inhibin B) is under study: interesting preliminary data about basal inhibin
level with a cutoff 20 pg/mL have been published [12].
Serum levels of Insulin growth factor-1 (IGF-1) in adolescent girls are physio-
logically related to pubertal stage more than to age, with a peak in late puberty [13].
Very low concentrations (less than two SD for age range) are a marker of congenital
or acquired Gh deficiency (as in thalassemia major); in constitutional delay of
growth and puberty (CDGP), IGF-1 levels are in agreement with growth and Tanner
stage, more than with chronological age. In situation of energy deficiency, such as
restrictive eating, an acquired growth hormone resistance with low IGF-1 levels is
present. As already mentioned, in subjects with hyperprolactinemia, not related to
pharmacological treatment, IGF-1 levels should be investigated in order to identify
mixed Gh and PRL secreting adenoma.
Blood tests should include serum creatinine to exclude kidney disease before
programming a brain RMI with gadolinium-containing contrast medium and the
anti-tissue transglutaminase (tTg) together with the dosage of IgA (to exclude mis-
leading results related to IgA deficiency). IgA endomysial antibodies (EMA) should
be required if IgA tTG is weakly positive and the use of IgG EMA, IgG deamidated
gliadin peptide (DGP), or IgG tTG should be considered if IgA are deficient.
In a second-level diagnostic workup, we include further tests:
1. To confirm the hypothesis of functional hypogonadism:

Body impedance analysis (BIA) or total body Dual X Ray absorptiometry
(DXA) to assess body composition: a significant reduction in fat mass as a per-
centage of body weight puts in evidence subject with BMI not so far from the
normal range, but with energy deficiency. This evaluation is also useful to esti-
mate the metabolic homeostasis in subjects with chronic diseases. It is manda-
tory to remind that we do not have standard references values for BIA in
peri-pubertal years, even if it has been demonstrated that fat mass increases in
the 6 months before menarche, reaching a plateau after around 1 year [14]. We
estimate as 18% of weight the fat mass necessary for the onset of menstrual func-
tion, considering that BIA underestimate fat measurement, in comparison to
DXA. The use of total body DXA is accurate, but expensive and minimally radi-
ant, so it find an indication when also an evaluation of bone mass deficiency is
necessary.
Hormonal markers of reduced energy availability as FT3, insulin, cortisol and
leptin (see Chap. 8)
Nutritional tests: folate, zinc, albumin, pre-albumin, transferrin, retinol-
binding globulin;
2. To study the possibility of hypothalamus-pituitary organic disease:
Magnetic Resonance Imaging (MRI) of brain and head with contrast medium
(gadolinium) should be performed if headache or neurological sings are present,
Kallmann or Charge syndrome are suspected, hyperprolactinemia has been
found, a Gh or other tropins deficiency are supposed, the clinical history orients
to iron overload and when hypogonadotropic hypogonadism without known eti-
ology is present. The exam can put in evidence the olfactory tract and bulbs
hypoplasia (Kallmann and Charge syndrome, septo-optic dysplasia), the pres-
ence of obstructive hydrocephalus, pituitary adenoma, empty sella, tumors com-
pressing the stalk or the hypothalamic region, pituitary infiltrates or autoimmune
hypophysitis (even if the differential diagnosis with pituitary adenoma is not
easy from a radiological point of view);
3. To evaluate the hypothesis of Gh deficiency:
Gh provocation tests (Insulin tolerance test of GhRH + arginine test);
4. To confirm the option of autoimmune hypophysitis:
APA, AHA, TPO Ab, TSHR Ab should be tested;
5. To differentiate HH with normal MRI from CDGP
GnRH test is largely used but the response in the two conditions show great
overlap. The choice of GnRH analogue test seems to be diagnostic, but the pub-
lished data are poor and the cut-off not univocal (LH/FSH ratio increase of 0.7,
after 2 or 3 h has been proposed as a confirmation of the possible activation of
hypothalamus-pituitary axis). It is useful also to evaluate estradiol production
24 h after the release injection [15]. The response to exogenous kisspeptin as
diagnostic test is under study;
6. Genetic testing is useful in hypogonadotropic hypogonadisms, in syndromic dis-
eases or in presence of additional phenotypic features, for diagnosis, prognosis
and genetic counselling to siblings.
2.3 Therapeutic Approaches
When a diagnosis of hypogonadotropic hypogonadism has been defined, a puberty

induction should start, to promote secondary sex characteristics, internal genitalia
growth and function. Current guidelines [16] advise the use of preferably transder-
mal estradiol starting with low-dose formulations, in order to mimic physiological
puberty [17]. If the diagnosis is evident at about 10 years of age it is possible to start
with 0.05–0.07 μg/kg nocturnally, obtained cutting 25 μg/kg patches and advising
the use of occlusive dressing if the patch tends to detach. If the girl is older, as usual,
the starting dose can be 0.08–0.12 μg/kg (at the beginning only during the night and
then with normal change of the patch twice a week) to promote breast development.
The dose is slowly increased every 9–12 months. As an alternative percutaneous or
oral estradiol can be chosen, using prepared pharmaceutical formulations with
equivalent dosages. The progesterone (100 mg per os) or dihydrogesterone, a pro-
gestin similar to progesterone from a metabolic point of view, (10 mg per os) should
be added for 12 days after at least 2 years of estrogen treatment, when spotting is
present or US endometrial thickness well documented (usually with an estradiol
dosage of 25 μg/kg/day). In girls with panhypopituitarism deydroepiandrosterone,
starting with 15 mg/day, should be added to promote pubarche. After the first men-
strual bleeding, the treatment must convert to a hormone replacement therapy,
increasing the transdermic estradiol dosage to at least 75 μg and redoubling the dose
of progesterone or progestin. Oral therapy with 2 mg of estradiol or with combined
natural estrogens and progestin is another option. A serum estradiol assay could be
used to check if hormonal concentrations are in the normal range for age. It is also
important to remind that in the future fertility will be possible using gonadotropins
or GnRH therapy.
In the rare cases of leptin deficiency a treatment with human recombinant leptin
may be proposed, starting with low dosages (0.04 mg/kg/day) given by subcutane-
ous injection at 6 p.m., adjusting the dose in order to achieve circulating level of the
hormone in the normal range for age and BMI.
In organic pathology of CNS the definition of the clinical situation and of the
best strategy of therapy require a strict cooperation with the neuroradiologist and
the neurosurgeon. An operation, to be performed in specialized units, is usually
indicated in cases of obstructive hydrocephalus, compressive pathologies, expan-
sive tumors. The use of intraoperative MRI can be a support. Considering the cra-
niopharyngioma, if the neoplasia does not invade the hypothalamus, the treatment
of choice is the complete excision of the tumor; if hypothalamic involvement is
present, the treatment consists in subtotal resection associated with postoperative
radiotherapy. The overall 5 years survival rate is 80%, even if it is associated with
marked morbidity (hypothalamic dysfunction, modifications of the neuropsycho-
logical profile). The treatment of autoimmune hypophysitis is medical and mostly
using corticosteroids, sometimes in association with azathioprin. In all the situa-
tions of persistent gonadotropin damage an endocrine therapy of pubertal induc-
tion and replacement is indicate, eventually associated with substitution of other
inadequate tropins.
In subjects with hyperprolactinemia related to microadenoma or stalk anomalies
not secondary to expansive pathology, a treatment with dopamine agonist (cabergo-
line, bromocriptine) can be started, in order to consent a normal pubertal develop-
ment, the attainment of bone mass peak and, frequently the reduction in the
dimensions of the tumor. To reduce possible side effects (nausea, orthostatic hypo-
tension) the bromocriptine should be started with a dose not more than 1.25 mg
daily and eventually increased; and the cabergoline with initial dose of 0.25 mg
once a week, then twice a week, checking prolactin levels. Only in prolonged treat-
ments with high dosages, it is advisable to program an echocardiographic control
for the rare possibility of cardiac valve alterations. Only in selected situations or
when the response to dopamine agonists is lacking a neurosurgical intervention can
be indicated. Concerning psychotropic drug-induced hyperprolactinemia, it is use-
ful to discuss with the psychiatrist taking care of the girl the possible options. The
choice is among the use of an alternative drug less active on dopamine receptor (as
aripiprazole as substitution or added at low doses) [18], the addition of dopamine
agonist to the treatment (not always effective and sometimes with the risk of wors-
ening the psychotic symptoms) or the possibility of starting a hormone therapy to
induce puberty and maintain menstrual function.
Gh deficiency requires a specific replacement treatment, able to promote growth
and pubertal progression.
The management of constitutional delay of growth and puberty is essentially a
follow-up supported by explanation and reassurance about its spontaneous evolu-
tion. In selected situations, the use of a short cycle of estrogen therapy has been
proposed, using a dosage related to the degree of development of secondary sex
characteristics (for instance 12.5–25 μg transdermal estradiol daily). This option,
above all justified by the psychological repercussions in the comparison with peers,
induces an acceleration in breast and genitals development and in linear growth,
combined with the spontaneous pubertal progression. The treatment does not influ-
ence final height, which results anyway slightly reduced in these subjects with
regard to their genetic target [19].
In functional hypogonadisms the therapeutic goal is usually to improve the gen-
eral health, suggesting for girls with eating disorders a psychological counselling
and an adequate nutritional support, for athletes a nutritional counselling and some-
times the reduction of intensity of training.
In coeliac disease, a gluten free diet is generally sufficient to promote a spontane-
ous pubertal development. In several chronic diseases, the pathogenesis of pubertal
delay is multifactorial: so it is important an in-depth evaluation of energetic and
metabolic homeostasis and, sometimes, of the therapeutic regimen. The treatment
plan should be evaluated also in adolescents with pubertal delay suffering from
endocrine dysfunctions; particularly in subjects with 21-hydroxylase deficiency
under treatment with hydroxycortisone, because pubertal endocrine milieu modifies
the metabolic clearance of cortisol but from the other side the linear growth is
extremely sensitive to a glucocorticoid excess. A reduction of dosages could some-
times be required to allow an adequate growth and sexual development [20].
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Diagnosis and Treatment of Genital
Malformations in Infancy 3
and Adolescence
Tiziano Motta and Chiara Dallagiovanna
Abbreviations
AFS American Fertility Society

AMH Antimüllerian hormone
ASRM American Society for Reproductive Medicine
DES Diethylstilbestrol
ESHRE/ESGE European Society of Human Reproduction and Embryology/
European Society of Gynaecological Endoscopy
GnRH analogues Gonadotropin-releasing hormone analogues
IVF In vitro fertilization
MIF Müllerian inhibitory factor
MRI Magnetic resonance imaging
MRKHS Mayer–Rokitansky–Küster–Hauser syndrome
MURCS Müllerian renal cervical somite
OHVIRA Obstructed hemivagina and ipsilateral renal anomaly
PID Pelvic inflammatory disease
TVS Transverse vaginal septum
US Ultrasonography
2D-US Two-dimensional ultrasonography
3D-US Three-dimensional ultrasonography
VCUAM Vagina, cervix, uterus, and adnexa-associated malformation
T. Motta (*) • C. Dallagiovanna

Department of Obstetrics and Gynecology, University of Milan, Fondazione IRCCS Cà
Granda Ospedale Maggiore Policlinico, Via Commenda, 12, 20122 Milan, Italy

36 T. Motta and C. Dallagiovanna
3.1 Embryology Development
The development of the female genital tract represents a complex process begin-
ning at 3–4 weeks of gestation and continuing into the second trimester of preg-
nancy. Until 8 weeks of gestation, the human fetus is sexually undifferentiated
and contains both male (Wolffian) and female (Müllerian) genital ducts. Wolffian
structures differentiate into the vas deferens, epididymis, and seminal vesicles.
Müllerian or paramesonephric ducts develop into the fallopian tubes (the unfused
cranial portions), uterus, cervix and, according to recent views, upper one-third
of the vagina [1]. In fact, there is general agreement that the vagina is a compos-
ite formed partly by the most caudal portion of the Müllerian ducts (sinovaginal
bulbs) and partly by the posterior wall of the urogenital sinus (vaginal plate): the
point of contact between the two is the Müllerian tubercle [2] (Fig. 3.1). This
dual origin theory best explains the various levels of vaginal obstruction that are
seen clinically. Otherwise most experts suggest that the vagina develops under
the influence of the estrogenic stimulation and the Müllerian ducts development
[3]. In the female fetus, without the influence of the müllerian inhibitory factor
(MIF), otherwise known as antimüllerian hormone (AMH), from week 8 to week
16 the Müllerian ducts undergo a process of elongation, fusion, canalization, and
septal resorption that will ultimately give rise to the abovementioned female
reproductive structures [4]. During this time, the Wolffian ducts regress; how-
ever, they are suggested to act as a guide in the downward growth of the Müllerian
ducts to form part of the vagina [5]. The cranial parts of the Wolffian ducts can
persist as the epoöphoron of the ovarian hilum; the caudal parts can persist as
Gartner’s ducts. The urogenital sinus also gives rise to the sinovaginal bulbs
which proliferate to form the hymenal tissue. The hymen is formed by expansion
of the caudal aspect of the vagina with the subsequent invagination of the poste-
rior wall of the urogenital sinus. It serves to separate the vaginal lumen from the
urogenital sinus cavity until late in fetal development. Normally it becomes
Fallopian
Lumen of
tube
uterus
Cervix
Uterine septum Fornix
Vagina
Caudal tip of Tissue of sinovaginal

paramesonephric bulbs (vaginal plate)
Urogenital sinus Hymen
ducts
Fig. 3.1 Embryonic formation of female reproductive system

3 Diagnosis and Treatment of Genital Malformations in Infancy and Adolescence 37
perforate before birth. The external genitalia of female and male are similar at
the indifferent stage of development between weeks 4 and 7. Distinguishing sex-
ual characteristics begins to appear at week 9, although full differentiation is not
achieved until week 12. Mesenchyme at the cranial aspect of the cloacal mem-
brane proliferates, forming the genital tubercle. In the absence of testosterone
and dihydrotestosterone, the genital tubercle develops into the clitoris, and the
labioscrotal folds do not fuse, leaving labia minora and majora. Because of the
close association of mesonephric and paramesonephric ducts, urinary tract
anomalies are frequently associated with female genital anomalies. Failure of
development of a Müllerian duct is likewise associated with failure of develop-
ment of a ureteric bud from the caudal end of the Wolffian duct. Thus, the kidney
can be absent on the side ipsilateral to the agenesis of the Müllerian duct.
Therefore it is extremely important that thorough urologic studies be performed
on all patients with Müllerian anomalies.
3.2 Etiology of Genital Malformations
The etiologies for the majority of congenital anomalies of the female reproductive
tract are largely unknown. Most structural anomalies of the internal reproductive
tract are a consequence of arrest at specific embryologic developmental stages.
Although the definitive etiology is often elusive, some genetic, intrauterine, and
extrauterine factors, as well as teratogens, such as diethylstilbestrol (DES) and tha-
lidomide, have been implicated [6]. The genetics of various congenital anomalies of
the reproductive tract are quite complex and go beyond the scope of this chapter.
Briefly, most cases occur sporadically. In familial cases, many anomalies appear to
be multifactorial. Associations with other modes of inheritance also exist and
include autosomal dominant and autosomal recessive patterns of inheritance as well
as X-linked disorders. Recently, HOX and WNT4 genes have been shown to play a
crucial role in sexual differentiation and female genital tract development, in par-
ticular during genital tract development. In fact, expression or function defects of
one or several HOX and WNT clusters may affect differentiation of Müllerian struc-
tures of the female reproductive tract [7, 8]. Müllerian anomalies can also represent
a component of a multiple malformation syndrome. Müllerian defects are associ-
ated with a higher incidence of other congenital anomalies, most notably those of
the urinary tract (20–25%), gastrointestinal tract (12%), musculoskeletal system
(10–12%), and heart, eye, and ear (6%).
3.3 Epidemiology
The true incidence of Müllerian duct anomalies is uncertain. Different authors have
described a wide range of prevalence rates depending on whether a general popula-
tion is evaluated at the time of obstetric delivery or has a history of infertility or
habitual miscarriage [9, 10]. March reported uterine anomalies in 0.1–2% of all
women, in 4% of infertile patients and up to 15% in women with recurrent abortions

[11]. The discrepancy in these prevalence rates presumably relates to the application
of different diagnostic methods, with variable test performance, and the use of dif-
ferent classification systems to define the abnormalities. More recently, Chan et al.
evaluated the prevalence of congenital uterine anomalies in unselected populations
and in women with infertility, including those undergoing IVF treatment, women
with a history of miscarriage, women with infertility and recurrent miscarriage
combined, and women with a history of preterm delivery [12]. The prevalence of
uterine anomalies diagnosed by optimal tests—i.e., three-dimensional ultrasonogra-
phy (3D-US), laparoscopy, or laparotomy performed in conjunction with hysteros-
copy or hysterosalpingography, MRI, and saline sonohysterography—was 5.5% in
the unselected population, 8.0% in infertile women, 13.3% in those with a history
of miscarriage, and 24.5% in those with miscarriage and infertility. The most com-
mon uterine anomaly diagnosed in these unselected population is the arcuate uterus
(3.9%), followed by the canalization defects (2.3%) and then the bicornuate uterus
(0.4%). This is not consistent with the findings from other studies or reviews, which
have generally found canalization defects to be the most common [9, 13, 14]. This
discrepancy is again likely to reflect the lack of a uniform system of classification
and possibly the misclassification of some arcuate uteri as normal or small subsep-
tate uteri.
3.4 Classification Systems of Genital Malformations
Various classification systems have been proposed to describe genital malforma-

tions. The first classification system was introduced by Strassmann in 1907 [15].
Actually, the most widely accepted is the ASRM (American Society for Reproductive
Medicine) classification system, formerly known as the AFS (American Fertility
Society) classification system. The classification, initially proposed by Buttram and
Gibbons in 1979 [16], revised and modified first in 1983 and then in 1988 by a sub-
committee of ASRM, is based on the degree of failure of Müllerian development
and fusion [17] (Fig. 3.2). The classification system is organized into seven basic
groups according to the major developmental failure and separates the defects into
groups having similar clinical manifestations, management requirements, and prog-
nosis. It also includes a class characterizing uterine abnormalities related to in utero
DES exposure. Additional findings referring to the vagina, cervix, fallopian tubes,
ovaries, and urinary system must be separately addressed. Despite being widely
accepted, the classification system has several drawbacks. It is unable to accurately
classify uteri, which demonstrate multiple anomalies that encompass several cate-
gories. In the setting of multiple dissimilar anomalies, it is imperative to describe
each anomaly as a component part, rather than attempt to classify it according to the
most dominant anatomic feature. Furthermore combined/complex malformations
(i.e., rudimentary uterus, cervical atresia, unilateral cervicovaginal atresia in a
didelphys uterus, and utero-cervical and/or vaginal septation) are not considered
and they are often incorrectly identified, inappropriately treated and sometimes
Fig. 3.2 American Society for Reproductive Medicine (ASRM) classification scheme for
Müllerian anomalies. Reproduced with permission from [17]
inaccurately reported. Other classification schemes have been developed. Toaff

et al. categorized the communicating uteri, rare uterine malformations characterized
by separate utero-cervical cavities connected through a communication [18].
Otherwise, Troiano and McCarthy suggested that the AFS classification should
function as a framework to describe anomalies, and that clinicians who are facing
complex/combined anomalies should describe them according to their component
parts rather than categorizing them into the class that most approximates the domi-
nant feature [19]. This approach, adopted by Acièn et al., could lead to a better
understanding of complex malformations before deciding on the best therapeutic
approach [20]. A newer classification system has been proposed to more accurately
characterize the genital malformations. It is an attempt to describe the genital anom-
alies based on their anatomic appearance, known as the “Vagina, Cervix, Uterus,
and Adnexa-associated Malformation” (VCUAM) [21]. The most recent ESHRE/
ESGE classification system “UCV” for female genital tract anomalies [22] incorpo-
rates concepts of the VCUAM classification and includes: (A) uterine anomalies
(U) with six main classes and (B) cervical (C)/vaginal (V) anomalies as coexistent
classes. Other anomalies are included as unclassified malformations (U6) and must
be described as associated anomalies of non-Müllerian origin. Although the classi-
fication system may be useful for scholarly research purposes, it is likely too com-
plex for widespread acceptance. In fact, this classification is yet to be widely
accepted among clinicians.
3.5 Diagnosis of Genital Malformations
In the pediatric population, most examinations of the external genitalia require

little in the way of instruments or supplies (a good light source, hand lens, or an
otoscope). The normal external genital structures are usually easily visible with
gentle, downward and lateral traction. In most of prepubertal girls, an otoscope
provides the magnification and light necessary to enable visualization of the

lower vagina but vaginoscopy is the ideal method to achieve an adequate com-
plete vaginal examination [23]; however, this is not routinely performed in the
office. In adolescence and young adulthood, office examination should entail a
detailed history, including menstrual features, and a confidential exam. Otherwise,
pelvic and/or rectal exam is the first step of evaluation for a vaginal or cervical
anomaly. Likewise, physical examination in an adolescent with primary amenor-
rhea and/or cyclic pain is essential, and evaluation of the external genitalia can
be facilitated through the use of traction on the buttocks to separate the labia
minora and visualize the vaginal introitus and hymen. A moistened q-tip can be
also used to probe the vagina. A speculum exam can be currently avoided in ado-
lescents and a Huffman speculum is appropriate for virginal adolescents aged
more than 10 years. In the past, in pediatric and adolescent patients, suspected
genital malformations were diagnosed primarily by laparotomy or laparoscopy.
Nowadays, some authors consider laparoscopy performed concurrently with hys-
teroscopy to be the gold standard in the diagnosis of congenital uterine anoma-
lies [14]. Despite being highly specific and accurate, laparoscopy (and
hysteroscopy) is an invasive procedure with potential morbidity, making it hard
to justify its use solely for diagnostic purposes in pediatric and adolescent popu-
lation. More recently, the development and refinement of ultrasonography (US)
and magnetic resonance imaging (MRI) have provided nonsurgical means of
obtaining an accurate diagnosis in most cases. US has proven to be of consider-
able importance in defining the nature and complexity of obstructive defects of
the reproductive tract in pediatric and adolescents patients [24–26]. In addition
to the vertical-fusion defects, US has been shown to be quite effective in identi-
fying lateral-fusion anomalies of the Müllerian duct system. In experienced
hands, a sensitivity of 92% and a specificity of 100% have been reported in the
assessment of bicornuate uteri [26]. Finally, the main point to keep in mind is
that ultrasound imaging of the uterus is most accurate in the luteal phase when a
thickened endometrial stripe will delineate the uterine cavity. The relatively
recent advent of 3D-US has allowed an increasingly accurate evaluation of con-
genital uterine anomalies, which are best evaluated during the secretory phase of
the menstrual cycle, when the endometrial echo complex is optimally visualized
[27]. Transvaginal 3D-US appears to be extremely accurate for the diagnosis and
classification of some congenital uterine anomalies, more than office hysteros-
copy [28] and likewise MRI [29]. It may conveniently become the only manda-
tory step in the assessment of the uterine cavity in patients with a suspected
septate or bicornuate uterus. Moreover, it has been recently demonstrated that
3D-US, if complemented by careful clinical examination, is comparable to MRI
in identifying anomalies of the cervix [30].
In conclusion, although US should be the initial examination of choice in patients
with suspected genital tract anomalies, MRI should be used to outline anatomy in
complicated cases. Actually, MRI has emerged as the universally accepted standard
in the imaging evaluation of genital malformations and has been considered the
gold standard imaging technique [31].
3.6 Symptomatic Genital Malformations
3.6.1 Imperforate Hymen
Imperforate hymen is the most frequent anomaly of the female reproductive tract,
occurring in 1/2000 girls [32] and it represents a persistent portion of the urogenital
membrane. Familial inheritance has been reported; however, no common genetic
trait has been recognized. Some reports suggest a dominant transmission [33], while
others suggest a recessive trait [34] or a multifactorial transmission. Antenatal diag-
nosis of imperforate hymen and hydrocolpos has been reported as early as the sec-
ond trimester [35]. In this case, drainage of the fluid should be the immediate
intervention in the neonatal period, postponing the final surgical procedure.
Occasionally, prepubertal girls can be referred with no obvious hymenal opening or
with a poorly visible microperforation (Fig. 3.3). In the absence of a collection,
definitive surgery should be deferred until the child is peripubertal. The imperforate
hymen is usually seen in girls in their early teens. On the clinical examination, the
hymen may be visualized as a bluish bulge at the perineum. Transabdominal or
translabial US may be used to confirm the diagnosis [36]. Depending on the circum-
stance, an imperforate hymen may not be detected until an adolescent girl has recur-
rent bouts of lower abdominal crampy pain but does not menstruate. The problem
may persist through several cycles until a pelvic mass becomes evident. This finding
is diagnostic and no further investigation is needed. A simple cruciate incision of the
hymen will release the menstrual flow and allow further normal menstruations.
Some authors prefer a U-shaped incision at the base of the hymenal membrane as it
maintains a normal hymenal remnant and avoids incision into the vaginal walls,
which can cause bleeding [37].
Fig. 3.3 Mucocolpos in a

newborn with an imperforate
hymen
3.6.2 Vaginal Atresia (Class I-a ASRM)
Vaginal atresia is a rare congenital defect resulting in uterovaginal outflow tract

obstruction. It occurs when the caudal portion of the vagina, contributed by the
urogenital sinus, fails to form. The caudal portion of the vagina is replaced with
fibrous tissue. Although not Müllerian in origin, vaginal atresia can clinically mimic
vaginal agenesis and imperforate hymen. Vaginal atresia, secondary adrenogenital
syndrome, and cloacal anomalies are beyond the aim of this chapter. Fifteen percent
of young patients with vaginal agenesis have segmental vaginal atresia [38] which
is usually referred to as complete or partial vaginal atresia (lower vaginal atresia)
(Fig. 3.4). Complete vaginal atresia is frequently associated with uterine agenesis,
known as the Mayer–Rokitansky–Küster–Hauser syndrome (MRKHS). The fallo-
pian tubes are normal, and the ovaries demonstrate normal endocrine function.
Partial vaginal agenesis is rarer and is characterized by normal uterus, normal cer-
vix, and small vaginal pouch distal to the cervix. Each examination of a newborn
should include an inspection of the genitalia, as absence of the vagina or complete
atresia could be detected during this simple evaluation. Complete vaginal atresia or
agenesis is usually diagnosed at puberty when young adolescents present with pri-
mary amenorrhea. In infancy, partial vaginal agenesis can present as hydrocolpos or
hydrometrocolpos; however, more commonly it occurs after menarche as a result of
trapped menstrual secretions and, similarly to imperforate hymen, the adolescent
girls are often in severe pain after only a few months of obstructed flow. Such pain
may be either cyclic or noncyclic, and is located in the pelvis or in the vagina,
Dilated uterus
with hematometra
Dilated vagina
with hematocolpos
Fibrous tissue
Fig. 3.4 Lower vaginal

atresia. Reproduced with Hymen
permission from [39]
depending on the patient’s anatomy. An abdominal mass can be sometimes palpated

and upon rectal exam a bulge is felt. 2D- and 3D-US and/or MRI confirm the pres-
ence of an obstructed upper vagina with hematocolpos and exclude the diagnosis of
cervical agenesis [40]. Percutaneous drainage may be temporarily necessary to
allow relief of pain and the facilitation of transfer of care to a tertiary center.
Definitive surgical correction is the therapy of choice. This goal can be established
by a vaginal pull-through procedure to create a new vaginal canal, with undermin-
ing and approximation of mucosal edges [41]. Postoperatively, wearing a vaginal
mold or initiating early vaginal dilation may further decrease the risk of vaginal
stenosis [10]. Incorrect diagnosis of the vaginal obstruction may result in excising
of the obstruction without mucosal approximation. This will lead to local scar for-
mation, recurrent partial or total obstruction, and difficulty in performing a second
surgical procedure.
3.6.3 Cervical Agenesis/Atresia (Class I-b ASRM)
Congenital absence of the uterine cervix associated with a functioning endometrium

is an extremely rare müllerian anomaly and occurs in 1 in 80,000 to 100,000 births
[42]. Rock et al. have organized cervical agenesis (or atresia) and dysgenesis (or
dysplasia) into four categories: cervical agenesis, cervical fragmentation, fibrous
cervical cord, and cervical obstruction [43]. When this anomaly occurs, it is known
to be associated in half of the cases with vaginal aplasia and with renal anomalies
[44]. Amenorrhea and cyclic lower abdominal pain are the first symptoms present-
ing in an adolescent, and can be associated also with upper abdominal pain and
fever if diagnosis is delayed. Endometriosis or pelvic infection may result from the
chronic hematometra. In some cases, hematosalpinx may also be present. Transrectal
ultrasonography and MRI can aid in defining anatomy [45]. Menstrual suppression
with GnRH analogues may be helpful in controlling symptoms while planning sur-
gery. The diagnosis and management of this Müllerian anomaly are both challeng-
ing and controversial. In the past, the surgical management of cervical agenesis has
been debated and the solutions offered have gone from hysterectomy with the cre-
ation of a neovagina [46], to the recanalization around stents of the rudimentary
cervix [47]. The surgical perspective in cases of cervical agenesis has evolved in
time. Early literature reports different attempts of canalization of cervical atresia
through cervical drilling or through catheter or pessary placement between the
uterus and vaginal vault, with or without simultaneous vaginoplasty [48–50]. Some
successful cases have been reported but the risks of conservative surgery (deadly
peritonitis, high failure rates, and poor functional results) far outweighed the bene-
fits. Consequently, it is not, thus, surprising that total hysterectomy with ovarian
conservation still offers numerous benefits and is supported as a treatment option by
several authors. Recent advances in reproductive technology and laparoscopic sur-
gical techniques mean that conservative surgery is a possibility and perhaps should
be considered as the first-line treatment option. Two series of patients treated for
this rare Müllerian anomaly with uterovaginal anastomosis have been reported.
Deffarges et al. [51] described 18 patients with cervical atresia, 7 of whom had
associated vaginal aplasia, and Chakravarty et al. [52] described 18 patients with
cervicovaginal atresia. In both series, menstruation was restored in all the patients.
In each of those series, two pregnancies were reported, both with delivery of viable
neonates. Complications reported by Deffarges et al. were two low vaginal stenoses
that were easily resolved and one cervical stenosis treated with multiple canaliza-
tion procedures leading to a pyosalpinx requiring salpingo-oophorectomy. In the
largest published series of 30 patients with cervical dysgenesis, Rock et al. [43]
recommended hysterectomy, as first-line of treatment option, in patients with com-
plete cervical agenesis and described successful creation of an adequate cervical
outflow tract in the subset of patients with cervical obstruction. An Italian study
performed in 12 adolescents (10 with complete cervical agenesis and 2 with cervi-
cal dysgenesis) confirmed that laparoscopically assisted uterovaginal anastomosis
may be considered the treatment of choice for patients with cervicovaginal atresia
[53]. The technique adopted by the authors was unique in performing hysterotomy
at the caudal end of the uterine corpus to ensure direct communication of the vaginal
mucosa to the endometrial lining. In conclusion, careful preoperative workup is
essential so that an accurate diagnosis is made prior to surgery. This congenital
condition is very rare and should be managed in specialist or tertiary centers with
not only surgical expertise but also access to multidisciplinary and wide-ranging
clinical support services.
3.6.4 Unicornuate Uterus (Class II ASRM)
The unicornuate uterus is caused by complete development of only one of the

Müllerian ducts, with absent development of the contralateral side. In cases where
the contralateral Müllerian duct develops only partially, the unicornuate uterus is
associated with a rudimentary horn, which may be cavitated or not cavitated and
may or may not communicate with the unicornuate uterus. A solitary uterine horn
can be observed in up to 35% of patients. More commonly (in 65% of cases), a
small rudimentary horn is seen arising from the primary single horn. A cavitated
non-communicating rudimentary uterine horn (class II-b according to the ASRM
classification) can be found in about 20–25% of women with unicornuate uterus.
There is a higher incidence of unicornuate horns on the right side which is not fully
understood [54]. A unicornuate uterine malformation is estimated to account for 5%
of all uterine anomalies, occurring in 1 in 4020 to 5400 women [55, 56]. Patients
can have an associated 40% risk of renal anomalies usually ipsilateral to the anoma-
lous side [57], 15% endometriosis, and, rarely, extrapelvic or absent ovaries [56].
Patients with cavitated non-communicating rudimentary horn present shortly after
menarche with increasing dysmenorrhea that is refractory to any treatment except
complete suppression with either combination hormonal therapy or GnRH analogue
with add-back therapy. Ultrasonographic imaging typically reveals a mass [58], but
anatomical assessment of the uterine structures is best accomplished through MRI
[59]; however, 3D-US has increased the sensitivity and specificity of this diagnosis
[60]. Laparoscopy is utilized to confirm the diagnosis and remove the non-
communicating functional rudimentary horn as treatment for dysmenorrhea, and to
prevent possible endometriosis caused by transtubal menstrual reflux and concep-
tion in an obstructed horn [55, 61].
3.6.5 Didelphys Uterus (Class III ASRM)
Didelphys uterus is a class III Müllerian anomaly based on the ASRM classification.
In the general population, the true incidence is unknown, but has been reported to
be between 0.1 and 3.8% [62]. For unknown reasons, anomalies of this type are
more common in the Finnish population, with an incidence of 0.5% [63]. This dis-
order occurs as a result of a complete or near-complete failure of the Müllerian
ducts to fuse. Each duct develops into an independent hemiuterus and cervix,
although partial cervical fusion is generally seen. A longitudinal vaginal septum can
be seen in up to 75% of cases [64] (see below Sect. 3.8). Without obstruction, didel-
phys uterus is asymptomatic. However, 6% of cases of vaginal septum with dupli-
cated cervix and uterus are characterized by unilateral obstruction of one hemivagina
by vaginal septum [65]. Didelphys uterus with obstructed hemivagina is associated
with ipsilateral renal agenesis [66–68]. This association has been first described in
the literature as Herlyn-Werner-Wunderlich syndrome. More recently, an acronym
OHVIRA (Obstructed Hemivagina and Ipsilateral Renal Anomaly) has been pro-
posed to describe this condition [69]. Patients may present at menarche with pro-
gressive dysmenorrhea secondary to hematometrocolpos, hematosalpinx, and
endometriosis, [70]. Occasionally, patients present with fever, peritonitis, purulent
vaginal discharge, and leukocytosis, leading to a presumptive diagnosis of PID [71].
It is only the finding of a double uterus and the absence of a kidney that will lead to
the correct diagnosis. In general, examination reveals an anterolateral bulge in the
vagina that makes it impossible to reach the cervix. In these cases, persistent post-
menstrual hemorrhage (sometimes malodorous) is characteristic before the patient
presents with pyocolpos in the obstructed vaginal canal. There is sometimes limited
inter-uterine (at the level of the isthmus) or inter-vaginal (at the vaginal apex) com-
munication. Furthermore careful examination of the vagina in these cases will
sometimes reveal a small opening in the otherwise obstructed vaginal septum that
may have allowed the migration of pathogenic bacteria. In the majority of cases,
regular menses from the communicating hemiuterus result in misdiagnosis and
increase the risk of unindicated procedures at the time of presentation [68, 69].
Occasionally, the condition can be diagnosed following acute urinary retention [72].
There are also some cases described in girls under 5 years of age [73]. Ultrasound
has proven to be accurate in the differential diagnosis of double uteri. In a study of
39 patients with technically adequate sonographic visualization of the uterus, trans-
abdominal US demonstrated a sensitivity of 100% and a specificity of 100% in
reaching the correct diagnosis of double uteri [74] (Fig. 3.5). MRI has been demon-
strated to be also accurate in discriminating between the various types of double
uteri. Fedele et al. reported a sensitivity of 100% and a specificity of 79% when
Fig. 3.5 2D Transvaginal

US. Longitudinal US scan
shows an hematocolpos (*)
and a dilated right hemiuterus
(**) in a 14-year-old girl with
Herlyn-Werner-Wunderlich
syndrome
Fig. 3.6 3D Transvaginal

US. Surface-rendered view of
a didelphys uterus at volume
ultrasound: on the coronal
plane, two divergent
independent hemiuteri and
cervix are noted
using MRI to differentiate between bicornuate, didelphic, and septate uteri [75].
Currently, 3D-US and especially MRI are the primary diagnostic tools but they are
limited to tertiary care centers (Fig. 3.6). In the meantime, MRI correctly anticipates
the diagnosis, but it is unable to accurately assess the presence of endometriosis,
pelvic infection, or adhesions that would affect future fertility. In these selected
patients, laparoscopy is highly recommended. In general, a single transvaginal sur-
gical procedure, including removal of the obstructed vaginal septum and marsupial-
ization of the blind hemivagina, solves the symptoms of this pathology. After the
septum has been excised (Fig. 3.7), laparoscopy can be performed for potential
treatment of associated endometriosis, adhesions, or both. In certain cases, hystero-
scopic metroplasty has been performed with simultaneous abdominal ultrasound to
evacuate and correct a complete septate uterus with unilateral hematometra [76, 77].
More recently, to avoid damage to hymen or cervices, vaginoscopy with resecto-
scope has been suggested [78, 79]. Women with non-obstructed didelphys uterus
Fig. 3.7 Longitudinal
incision of the vaginal
septum in a young patient
with OHVIRA
are usually not candidates for surgical unification. The decision to perform metro-
plasty should be individualized, and only selected patients may benefit from surgi-
cal reconstruction. Most reports of metroplasty in this setting are anecdotal and lack
the statistical power of randomized studies. Therefore, the apparent benefits of sur-
gery are not clear.
3.6.6 Transverse Vaginal Septum
TVS results from failure of fusion between the müllerian ducts and the urogenital
sinus or abnormal vaginal canalization. A TVS can divide the vagina into two seg-
ments and thereby reduce its functional length. A TVS can be imperforate or perfo-
rate, and vary in its thickness and location in the vagina. Most of them are located
in the superior vagina (46%). The next most common locations are the mid vagina,
at a rate of 40%, and the inferior vagina, at a rate of 14% [80]. A TVS is relatively
uncommon, with a reported incidence varying greatly from 1 in 2100 to 1 in 84,000
females [81–83]. Unlike other Müllerian duct anomalies, TVS is only occasionally
associated with urologic defects but it has been associated with other structural
anomalies, including imperforate anus, bicornuate uterus, coarctation of the aorta,
atrial septal defect, and malformations of the lumbar spine. TVS is rarely diagnosed
in the neonate or infant unless the obstruction causes a significant hydromucocol-
pos. Hydromucocolpos can be diagnosed in utero during a third-trimester transab-
dominal ultrasound. Early delivery and drainage of the obstructed vagina and uterus
are indicated when other organs are compromised [84]. In infants, the vaginal sep-
tum is usually thin (<1 cm thick) and can be corrected without extensive procedures.
Clinical follow-up is necessary because vaginal stenosis with subsequent accumula-
tion of fluid may develop postoperatively. In adolescence, imperforate septum pres-
ents with obstructed menstruation and hematocolpos [85]. A presence of a palpable
pelvic mass and a perineal bulge can be often revealed depending on level and loca-
tion of the imperforation during the physical examination. In these patients, cyclic
abdominal pain, vaginal discharge, amenorrhea, or abnormal menstruation, and

occasionally urinary retention may be present at the postpubertal stage. Moreover,
retrograde blood flow through the uterus and the fallopian tubes resulting from
imperforation may predispose these patients to develop severe endometriosis in
2–56% of cases [65, 86]. Women with a perforate septum often have normal menses
and usually present with dyspareunia and difficulty in inserting tampons into the
vagina [85]. Initial evaluations should include an abdominal US of the pelvis [87].
Imaging should include an assessment of the renal anatomy since up to 20% of
cases have associated renal anomalies. The diagnosis can be confirmed on MRI,
especially if a strong clinical suspicion exists. MRI can also be useful to determine
the thickness of the vaginal septum preoperatively. It is also extremely important to
identify a cervix on US or MRI in order to differentiate between a high septum and
cervical atresia. The surgical approach to TVS excision depends on the character,
thickness, and location of the septum. The TVS is most frequently less than 1 cm
thick and can be treated by excision and end-to-end anastomosis of the vaginal
mucosa. The TVS can be thick in the adulthood, rendering its removal more difficult
than in the infant. While thick septa require complex surgery often necessitating
reconstruction using grafts or flaps, thin TVS can be managed considerably more
easily [88]. Treatment involves surgical resection of the septum and anastomosis of
the upper and lower vaginal mucosa, usually followed by vaginal dilatation. It can
be performed vaginally, laparoscopically, or via an abdominoperineal approach,
depending on the location and thickness of the septum [80, 88]. Common problems
of these techniques include shortening of the vagina due to septal tissue excision
and postoperative stenosis of the vagina owing to the formation of constricting
fibrous bands during the healing process. A Z-plasty technique may help to prevent
circumferential scar formation [89–91]. More recently, Arkoulis et al. have pro-
posed a simple technique for the surgical management of thin septa, utilizing two
interdigitating Y-plasties, without the need for excision of any septal tissue. The
authors presented their small series of eight consecutive cases where this technique
was used, with no major complications or any case of vaginal re-stenosis [92]. In
general, regardless of the technique used for postoperative dilation, it is very impor-
tant to do an entire septum resection and to try to prevent stenosis and scarring,
which is common after a transverse septum resection. For difficult cases, a probe
can be passed transfundally through the uterus, down through the endocervical
canal, and into the upper vagina so as to tent up the septum and aid in the resection.
For more extreme and complex cases, vaginoplasty may be indicated. Complications
may be significant and include vaginal stenosis and re-obstruction (recurrence),
dyspareunia, endometriosis, infertility, obstetric complications, and psychological
difficulties. It is essential that accurate information on the septum is available to
ensure that the correct operative approach is chosen.
In conclusion, transverse vaginal septum should be managed within specialist
centers for complex gynecology with experience in managing congenital gyneco-
logical anomalies. However, knowledge of the clinical presentation and manage-
ment of these abnormalities is important, as it can prevent misdiagnosis and
unnecessary delays in specialist referrals.
3.6.7 Longitudinal Vaginal Septum
Incomplete resorption of the Müllerian ducts and urogenital sinus may cause the
formation of a longitudinal vaginal septum. A longitudinal vaginal septum is associ-
ated with a uterine anomaly (septate or didelphys uterus) in 95% of cases [86].
Conversely (as previously stated), patients with uterine duplication have a concur-
rent longitudinal vaginal septum in 75% of cases [64]. The presence of a duplicated
cervix is indicative of either didelphys or complete uterine septum. The septum may
be complete or partial. In some cases where the septum is complete, it may be bilat-
erally (uterus didelphys, bicollis, with complete vaginal septum with bilateral
obstruction) or unilaterally imperforate and symptomatic (see didelphys uterus).
Non-obstructed longitudinal partial vaginal septum is typically asymptomatic and,
occasionally, the patient will complain of bleeding despite the placement of a tam-
pon. Currently, it may not present at all until pregnancy when it is an incidental
finding. In some cases the patient may complain of a hooked tampon or pain with
coital activity, which may be secondary to bruising of the septum [83]. The partial
septum should be removed only if symptomatic or if the woman desires restoration
of a normal vaginal canal. Prior to initiating the surgery, a Foley catheter is placed
in the bladder. Since these septa are typically well vascularized, Kelly clamps are
systematically applied to the anterior and posterior portion of the septum and then
cut with a knife or electrocautery device. It is not usually necessary to excise the
complete septum as the tissue retracts and leaves a narrow ridge that is of no conse-
quence. Hemostasis is secured by placing a continuous locking suture, absorbable
(00) on each edge of the divided septum [93]. As the tissue can be very thick, atten-
tion to hemostatic control is always essential.
3.7 Asymptomatic Genital Malformations
3.7.1 Vaginal Agenesis (Class Ie ASRM)
Vaginal agenesis, also known as Müllerian aplasia or MRKHS, is the congenital

absence of the vagina with variable Müllerian duct in otherwise phenotypically nor-
mal 46, XX females. The uterus and cervix in such patients are more often absent;
however, 7–10% of such women have a rudimentary uterus with functional endo-
metrium [94], and as many as 25% have cavitated müllerian remnants [95, 96]. The
fallopian tubes are frequently normal; however, they may be hypoplastic or mal-
formed [97]. The ovaries demonstrate normal endocrine function [98]. The preva-
lence of MRKHS is given as 1 in 4500–5000 newborn females [99]. This is based
on a single study from Finland and does not allow similar predictions for other
populations. MRKHS is generally divided into three subtypes: MRKHS (typical or
type I), MRKHS (atypical or type II), and MURCS (Müllerian Renal Cervical
Somite) association or type III. Anatomic examination is required for differential
diagnosis of specific MRKHS types. MRKHS type I accounts for approximately
44% of MRKHS cases and is characterized by complete uterus aplasia in the
presence of two symmetric rudimentary horns linked by a peritoneal fold, normal

fallopian tubes, ovaries, and renal system [100]. MRKHS type I is rarely associated
with clinical signs of hyperandrogenism [101]. MRKHS type II is the most frequent
form of MRKHS, accounting for approximately 56% of cases [100]. It is character-
ized by uterine symmetric or asymmetric hypoplasia, accompanied by aplasia of
one of the two horns or by a size difference between the two rudimentary horns,
with or without dysplasia of one or both of the fallopian tubes. MURCS association,
which represents the most severe form of MRKHS, is characterized by Müllerian
duct aplasia/hypoplasia, renal agenesis/ectopy (in 25–50% of patients), and cervi-
cothoracic somite dysplasia (Klippel–Feil syndrome) (30–40%)[102]. In this form,
other less common associated anomalies such as heart defects, hearing impairment,
syndactyly or polydactyly are often observed [103]. MRKHS is mainly sporadic;
however, familial cases have been described indicating that, at least in a subset of
patients, MRKHS may be an inherited disorder [104, 105]. The syndrome appears
to demonstrate an autosomal dominant inheritance pattern, with incomplete pene-
trance and variable expressivity. The etiology of MRKHS is still largely unknown,
probably because of its intrinsic heterogeneity. Several candidate causative genes
have been investigated, but to date only WNT4 has been associated in a few cases
with MRKHS patients with hyperandrogenism [106]. The development of second-
ary sexual characteristics occurs normally, thus the diagnosis of MRKHS is gener-
ally made late, at the beginning of puberty, due to the lack of onset of menstruation
(primary amenorrhea) or, seldom, due to the impossibility of sexual intercourse.
Indeed, vaginal agenesis is the second most common cause of primary amenorrhea
in adolescents [107]. Functional endometrial tissue in an obstructed uterine remnant
can rarely cause cyclic pelvic pain from hematometra, hematosalpinx, and endome-
triosis [108]. When it is expected to have a suspicion of Müllerian anomalies,
2D-US and renal US represent the first assessment survey to exclude urinary tract
anomalies [37]. An MRI may be more accurate in the evaluation of müllerian struc-
tures, but given the expense, it can be reserved for when ultrasound is indeterminate
[19]. Because transabdominal 2D-US and MRI are not always reliable in providing
a clear-cut diagnosis on the presence of endometrium in the uterine horns, Fedele
et al. have recently demonstrated the use of an endoscopic ultrasound probe in the
evaluation of the structure of the rudimentary uterine horns in MRKHS, with spe-
cific regard to the identification of the endometrial cavity and its localization inside
the myometrial structure, as well as the identification of the vascular structures of
the rudiment [108].
Laparoscopy is not usually indicated unless the diagnosis cannot be determined
on findings from other studies or if a concern exists regarding the presence of a func-
tioning uterus or rudimentary uterine tissue. Evaluation of the patient with near total
or complete vaginal agenesis, like other Müllerian anomalies, begins with a genital
examination (Fig. 3.8). Most patients will have a vaginal dimple or very foreshort-
ened, blind-ending vagina. The hymenal fringe is usually present along with the
small vaginal pouch, as they are both embryologically derived from the urogenital
sinus. A pelvic mass will usually be absent and occasionally a peritoneal fold can be
palpated on recto-abdominal bimanual examination. Management of these patients
Fig. 3.8 A preoperative

perineal photograph
demonstrating the absence of
the vaginal opening in a
patient with MRKHS
requires attention to two distinct areas: (a) the management of the congenital anom-
aly itself, in order to allow the patients to become sexually active and (b) the manage-
ment of the psychological impact of such condition [82]. For many reasons,
psychological support and counseling are essential components of the preoperative
evaluation and care. Young patients with MRKHS suffer from extreme anxiety and
very high psychological distress when they are told they have no uterus and vagina.
Thus, it is suggested that patients and their families attend counseling before and
throughout treatment. Group programs and MRKHS associations are also of great
help [109]. In addition to the inability to have sexual intercourse, these young women
are usually infertile, resulting in psychological pain and self-esteem issues [110].
Initially, the management of this malformation is usually based on a nonsurgical
method and then, if necessary, on a surgical approach. In the last 10 years, literature
has significantly supported the nonsurgical approach as the first line for the creation
of the neovagina [111]. The nonsurgical technique involves the repeated use of grad-
uated vaginal dilators [112] over a period of 6–12 months (Fig. 3.9). This will be
successful in about 95% of cases when appropriately selected [113]. This method
must be tried initially in all girls with absent vagina and a 1 cm deep dimple.
Historically, Ingram suggested the use of a dilator put on a modified bicycle seat
[114], whereas D’Alberton et al. and Motta et al. have reported a success in 95% of
the patients who have undergone a dilatation of retrohymenal pit by using coitus
[115, 116]. Furthermore, particular care must be taken not to dilate the urethra, which
can lead to urinary incontinence. For those girls with less than 1 cm of vagina or
those in whom Frank’s maneuver fails, surgery will be required. Surgical creation of
a neovagina is an option not only for young women who fail nonoperative dilation
therapy but also for those who choose surgery after a thorough discussion with the
patient (and parents/guardians as indicated) regarding the advantages and disadvan-
tages. Currently, there are multiple operations appropriate for the creation of a neo-
vagina in patients with vaginal agenesis but there is no consensus on the best
approach. The creation of a neovagina should certainly be performed in only a
Fig. 3.9 A set of vaginal

dilators
limited number of centers and the procedure of choice should also be determined by
the surgeon’s experience and success with the procedure because reoperation
increases the risks of injury to surrounding organs. Among the historical operative
procedures, the Abbè–McIndoe procedure [117, 118] (Fig. 3.10), the Williams vagi-
noplasty [119], the Creatsas’ modified Williams vaginoplasty [120], the Vecchietti
method [121] as well as the Davydov method [122] were frequently used. New surgi-
cal methods, in which laparoscopy has replaced traditional surgery, have recently
been developed. Among these sigmoid colpopoiesis [123, 124] has been suggested,
although Fedele’s modified Vecchietti technique [125] and Davydov’s method modi-
fied by Adamyan et al. [126] and by Soong et al. [127] are the two most adopted lapa-
roscopic procedures. The modified laparoscopic Vecchietti procedure creates a
dilation-like neovagina in 7–9 days. It involves placement of a pluggable segmented
dummy onto the vaginal dimple that is gradually pulled superiorly by threads laparo-
scopically placed that are then connected to the traction device placed on the patient’s
abdomen (Fig. 3.11). The threads are then gradually tightened approximately 1.0–
1.5 cm per day for a week. Postoperatively, the patients must comply with daily vagi-
nal dilation until regularly sexually active. The main goal of laparoscopic Davydov’s
technique is to make a neovagina using the patient’s own pelvic peritoneum as cover-
ing. It involves dissection of the perineum to create a neovaginal space while laparo-
scopically mobilizing the peritoneum. The peritoneum is then sutured to the introitus
and a purse-string suture closes the cranial end of the neovagina. A soft vaginal mold
is left in situ for 6 weeks and then vaginal dilators are kept for 30 min a day to main-
tain a suitable vaginal length until regularly sexually active. The Vecchietti’s and
Davydov’s laparoscopic techniques have been recently compared in an Italian study
[128]. Vecchietti’s laparoscopic technique is definitely simpler and faster owing to its
unique laparoscopic step, whereas the modified Davydov’s procedure also requires a
perineal step which can be complex. Epithelization of the neovagina at 6-month fol-
low-up was 60% and 80%, respectively, and 100% in both groups at 12 postoperative
months, as it has been previously suggested [129]. Davydov’s procedure is particu-
larly indicated for patients with abnormalities of the external genitalia, such as
Fig. 3.10 Perineal
photograph taken
intraoperatively after
creation of the neovagina
with split-thickness skin
graft (McIndoe procedure)
Fig. 3.11 The traction device required for Vecchietti laparoscopic operation
female hypospadia, which is a contraindication to the creation of a neovagina by

vaginal pressure, such as in the laparoscopic Vecchietti technique and Frank method.
Otherwise, patients with a pelvic kidney are not assigned to Davydov’s procedure
group but rather to Vecchietti’s procedure owing to the risk of damaging the pelvic
kidney or ureter during laparoscopic mobilization of the peritoneum. Similarly, pre-
vious pelvic surgery might be a relative contraindication to Davydov’s technique
because the presence of postoperative adhesions might complicate the surgical pro-
cedure and increase the risk of intraoperative complications. Finally, in view of the
possibility of offering uterine transplantation to these patients, the disruption of the
pelvic anatomy caused by Davydov’s approach might likely preclude such proce-
dure, whereas Vecchietti’s technique leaves the anatomy of the intrapelvic structures
unaltered. As previously reported, in patients with MRKHS, rudimentary uterine
horns are frequently cavitated. In the majority of cases, there is no evidence of endo-
metrial functioning (hematometra), and in fact only a small number of cases experi-
enced cyclic pain symptoms. Such finding warrants a systematic search of this
anatomic characteristic to provide, before corrective surgery, an adequate counseling
on the therapeutic possibilities, i.e., the removal of cavitated and symptomatic uter-
ine remnants or the attempt to anastomose them to the vaginal vestibulum. The latter
procedure has been described by the same Italian research group in a recent report
[130]. The traditional motherhood options for women with MRKHS are adoption or
use of a gestational surrogate carrier with their own oocytes through IVF [131, 132].
Importantly, gestational surrogate pregnancies with MRKHS women as genetic
mothers do not seem to have any increased risk of fetal uterine malformation, which
would indicate that epigenetic changes may be behind this syndrome [133]. Up to
now, there have been 11 human uterus transplantations with 5 successful deliveries
[134]. So far, MRKHS has been the main indication for uterus transplantation with
nine patients being transplanted [135, 136].
3.7.2 Bicornuate Uterus (Class IV)
The bicornuate uterus is classified as a class IV Müllerian duct anomaly. This condi-
tion is the result of the incomplete fusion of the two Müllerian ducts at the level of the
uterine fundus and is characterized by two divergent uterine horns that fuse at the level
of the lower uterine isthmus. A muscular uterine septum is also present and classifica-
tion depends on its extent. When the septum extends to the internal os, the anomaly is
considered complete; this is known as a bicornuate unicollis uterus. Another variant of
the complete form of bicornuate uterus is the bicornuate bicollis uterus, in which the
septum extends to the external os. This anomaly has been described in approximately
25% of patients with bicornuate uteri. When the septum is confined to the fundal
region, it is considered a partial bicornuate uterus. The external uterine contour has an
indented fundus, arbitrarily defined as more than 1 cm, and is sometimes referred to
as “heart shaped”; the vagina is generally normal [19, 74, 75]. Bicornuate uterus is
considered an incidental finding in child- and adolescenthood. Young patients are usu-
ally asymptomatic and have no difficulty becoming pregnant. Such anomaly is
associated with obstetrical complications including cervical incompetence, preterm

labor, and malpresentation. Evaluation of bicornuate uterus should begin with ultra-
sound during the luteal phase of the menstrual cycle, when the endometrium is echo-
genic and thickened, resulting in a clear distinction between the endometrial cavity
and the myometrium. In the past, 2D-US and hysterosalpingography did not effec-
tively distinguish between septate and bicornuate uterus. Findings of the uterine fun-
dus can also be achieved with abdominal US performed with a semi-full bladder in the
secretory phase of the menstrual cycle visualizing the tubal ostia and the region of the
internal cervical os. If there is no indentation of the perimetrial fundal profile, or when
such an indentation is less than 5 mm below the imaginary line joining the two tubal
ostia, then the uterus is septate. On the other hand, when such a fundal indentation is
identified and is 5 mm or more below the abovementioned line, the uterus is bicornu-
ate or didelphic [74, 137]. MRI is very effective in characterizing uterine anomalies;
however, it is costly and has limited availability. More recently, transvaginal 3D-US
has allowed the visualization of both the uterine serosa and the endometrium with less
cost than an MRI. When compared with the gold standard of concurrent hysteroscopy
and laparoscopy, 3D ultrasound has similar accuracy in correctly identifying the spe-
cific anomaly [138]. Otherwise, it is extremely important to correctly differentiate a
septate uterus from a bicornuate one, for which surgical intervention is not indicated.
Non-uterine causes of infertility must be ruled out before metroplasty is considered as
last resort. The Strassman metroplasty should be reserved for selected women based
on poor reproductive outcomes.
3.7.3 Septate Uterus (Class V)
Septate uterus is the most common uterine anomaly with a mean incidence of 35%
[14]. It results from incomplete resorption of the medial septum after complete
fusion of the müllerian ducts has occurred. The septum, which is located in the
midline fundal region, is composed of poorly vascularized fibromuscular tissue
[139]. Numerous septal variations exist: the septum is considered complete (Class
V-a) if it extends to the internal os (and beyond), thus dividing the endometrial cav-
ity, and partial (Class V-b) if it does not. A complete uterine septum is typically
diagnosed in young adulthood. Such malformation can be associated with a longi-
tudinal vaginal septum, in approximately 25% of cases, separating the vagina itself,
either partially or all the way to the introitus [140]. In addition, septa may be seg-
mental, which results in partial communication between the endometrial cavities
[141]. As previously mentioned, visualization of the uterine fundus is crucial to
reliably differentiate between a septate and bicornuate uterus. Today, the diagnosis
of septated uterus is readily made with hysteroscopy and its accuracy is close to
100% [142]. 2D-US is a good noninvasive method to evaluate the uterine cavity.
The sensitivity of this method to diagnose a septated uterus is 81% [143]. Three-
dimensional US is more accurate and is better in distinguishing between septated
uterus and bicornuate uterus. The accuracy of 3D-US in detecting uterine septa is
92% [142]. Using 3D-US with the injection of saline to the uterine cavity as contrast
medium has increased the sensitivity to 98% and specificity to 100% in the diagno-
sis of septated uterus [142]. When the abovementioned method fails, an MRI, which
has a sensitivity of 100% and specificity of 79% in detecting intrauterine lesions,
may be used [142]. A uterine septum affects female reproductive health in three
ways: (a) obstetrical complications, (b) recurrent miscarriages, and (c) infertility
[144]. Although clinical studies consistently demonstrate a poorer obstetric out-
come in patients with septate uterus compared to women without uterine anomalies
[9, 145], literature on septate uterus as the primary cause of female infertility is
controversial. A septate uterus is generally amenable to hysteroscopic resection of
the septum, whereas surgical intervention does not improve reproductive outcome
in patients with bicornuate uterus. There are several minimal invasive surgical tech-
niques available in order to remove the septum; the hysteroscopic metroplasty by
resectoscopy is considered the first therapeutic option [146].
3.7.4 Arcuate Uterus (Class VI)
The arcuate uterus is classified as a class VI Müllerian duct anomaly. It is character-

ized by a small septate indentation at the superior aspect of the uterine cavity in the
fundal region and it usually demonstrates a normal external fundal contour.
On 2D-US, a single endometrial cavity is frequently noted. Three-dimensional
US permits to obtain planar reformatted sections through the uterus, which allow
both the precise evaluation of the fundal indentation and the length of the septum.
On MRI, the arcuate uterus demonstrates a normal external fundal contour and a
smooth indentation of the endometrial canal by a broad-based myometrial promi-
nence. The prominent fundal myometrium shows normal myometrial signal inten-
sity, with no hypointensity to suggest fibrous tissue. Rarely symptomatic and rarely
associated with adverse reproductive outcomes, arcuate uterus has been advocated
by some authors to represent a true anomaly, whereas others consider it a normal
variant rather than a true anatomical or developmental anomaly [147]. In the last
years, hysteroscopic resection of subseptations has become routine in clinical prac-
tice, especially in fertility clinics, in which surgery is undertaken before performing
costly fertility treatments in an attempt to decrease the risk of miscarriage in a future
pregnancy. Otherwise, a recent retrospective study, as previously demonstrated for
the first time by Fedele et al. [148], underscored the importance of subseptation
resection in patients with infertility for the sole purpose of ameliorating fertility
outcomes, independently from obstetric outcomes [149].
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Gonadal Failure
4
Maria Francesca Messina and Alfonsa Pizzo
4.1 Introduction
The gonads are the primary reproductive organs; in males, the gonads are the testes
and, in females, the gonads are the ovaries. These organs are necessary for sexual
reproduction, as they are responsible for the production of male and female gametes
(a cell that fuses with another cell during fertilization).
Gonads also produce the sex hormones needed for the growth and development
of primary and secondary reproductive organs and structures.
Gonadal activation starts in puberty with the pulsatile secretion of gonadotropin-
releasing (GnRH) hormone that stimulates pituitary release of luteinizing hormone
(LH) and follicle-stimulating hormone (FSH).
This hormonal cascade results in gonadal maturation with subsequent production
of sex steroids, nonsteroidal factors, and gametes. The physical changes in puberty
culminate in sexual maturity and reproductive capacity [1].
During the first months of life, the hypothalamic-pituitary-gonadal (HPG) axis is
active (termed mini-puberty) and results in sex hormone levels near adult concentra-
tions [2]. The hormonal dynamics of the neonatal mini-puberty represent the first
opportunity to observe the activity of the HPG axis before adolescence, as child-
hood is a period of quiescence with low GnRH secretion. Episodic GnRH secretion
resumes in early puberty with nocturnal, pulsatile GnRH secretion that extends pro-
gressively through the day and is sustained throughout adult life.
Gonadal failure, also known as hypogonadism, is what occurs when the gonads
cease functioning as efficiently [3, 4].
This diminished functioning may result, in females, in low estrogen levels, in
addition to a decrease in other hormones produced by the gonads. Ovulation may be
M.F. Messina (*) • A. Pizzo

Department of Human Pathology of Adulthood and Childhood, University of Messina,
Messina, Italy

64 M.F. Messina and A. Pizzo
impaired, and this may then result in partial or complete infertility. This deficiency
of the sex hormones can also result in defective sexual development if gonads cease
functioning in prepubertal age or in withdrawal effects (premature menopause) if it
happens in adults. Mostly, these effects are permanent.
Hypogonadisms may be distinct in two main distinct entities: hypogonadotropic
or central hypogonadism and hypergonadotropic hypogonadism (ovarian insuffi-
ciency) [5].
Moreover, the failure of the gonads may be caused by both congenital and
acquired disorders.
4.2 Etiology
4.2.1 Hypogonadotropic Hypogonadism
Absent or partial puberty in association with low serum sex steroids in the setting
of low or inappropriately normal serum gonadotropin levels defines hypogonado-
tropic hypogonadism (HH). It can be attributed to a variety of congenital origins
including single gene mutations, idiopathic forms, and genetic syndromes [5].
Acquired causes of HH include central nervous system (CNS) insults such as
trauma, irradiation, and intracranial tumors (Table 4.1). The most common cause
of HH is transient and is termed constitutional delay of growth and puberty
(CDGP), a variation of normal development, more frequent in males than in
females, in which puberty and pubertal growth spurt occur at or later than the
extreme upper end of the normal range.
Table 4.1 Causes of hypogonadism

Hypergonadotropic hypogonadism Hypogonadotropic hypogonadism (hypothalamic-
(ovarian insufficiency) pituitary defects)
Congenital Congenital
– Turner syndrome – Kallmann syndrome
– Primary ovarian insufficiency – Isolated hypogonadotropic hypogonadism (IHH)
– Abnormalities in gonadotropin – Combined pituitary hormone deficiency
production or action
– Galactosemia – Transcription factor mutations
– Gonadal dysgenesis – Leptin and leptin receptor defects
– X chromosome abnormalities – Syndrome (Laurence–Moon–Biedl, CHARGE)
Acquired Acquired
– Autoimmune destruction – Traumatic brain injury
– Chemotherapy – Central nervous system diseases (tumors, infections,
autoimmunity, infiltrative diseases)
– Radiation – Functional hypothalamic amenorrhea (Eating
disorders, athletes amenorrhea, stress, obesity)
– Iatrogenic (irradiation, corticosteroids)
– Medical condition (chronic diseases, hypothyroidism,
Cushing syndrome, hyperprolactinemia, etc.)
4 Gonadal Failure 65
Congenital forms are clinically characterized by absent or partial puberty and

infertility. Biologically, HH is characterized by low or normal serum levels of LH
and FSH in the setting of low sex steroids. Typically, patients with HH present in
adolescence or early adulthood with delayed onset of puberty, primary amenorrhea,
poorly developed sexual characteristics, and/or infertility.
4.2.1.1 Congenital Origins

Kallmann syndrome: This syndrome refers to the combination of hypogonadotropic
hypogonadism and anosmia. The mutation of KAL1 gene results in a defect in the
migration of GnRH and olfactory neurons. Individuals with KS have hypothalamic
GnRH-secreting deficiency and aplasia of the olfactory bulb as noted on magnetic
resonance imaging (MRI). The inherited mechanism may be X-linked or
autosomal.
Isolated hypogonadotropic hypogonadism (IHH): One potential cause is loss of
function mutations of the GnRHR, a G-protein coupled receptor (more than 25 loci
have been shown and several European centers offer genetic screening, www.orpha.
net and www.gnrhnetwork.eu). Genotype–phenotype variations exist even within
members of the same kindred. Females typically present with primary amenorrhea.
IHH has been noted to be reversible in 10–20% of HH patients.
Combined pituitary hormone deficiency: HH can be present as part of a broader
pituitary deficiency disorder (CPHD). It is defined as the presence of two or more
pituitary hormonal deficiencies. In some case, neonatal signs such as hypoglycemia
can point to a CPHD diagnosis early in life, yet adolescents present for evaluation
with absent/partial puberty and short stature.
Transcription factor mutations: Even with intact GnRH production and signal
transduction, pituitary gonadotropin synthesis may still be deficient due to muta-
tions in a variety of transcription factors. An important transcription factor is Prop-
1, the prophet of the pituitary transcription factor Pit-1. Prop-1 gene mutations can
result in familial combined pituitary hormone deficiency including growth hormone
deficiency, central hypothyroidism, and hypogonadotropic hypogonadism. HESX-1
is a transcription factor needed for normal pituitary development; its deficiency can
be responsible of septo-optic dysplasia and hypogonadotropic hypogonadism. Other
transcription factors implicated in rare causes of hypogonadotropic hypogonadism
are LHX4 and SOX2.
Leptin and leptin receptor defects: Leptin deficiency acts as a sign of nutritional
deprivation and results in the suppression of the reproductive axis. Classical find-
ings in individual with leptin deficiency include hyperphagia, obesity, and hypogo-
nadotropic hypogonadism. Girls with LEP (leptin) or LEPR (leptin receptor) gene
mutations present with delayed puberty, lack of a pubertal growth spurt, and reduced
expression of secondary sexual characteristics.
Syndromes: Numerous syndromes include neuroendocrine dysfunction. The best
known is Prader–Willi syndrome (PWS), caused by a genetic defect involving
paternal chromosome 15 or maternal disomy. In these patients, hypogonadotropic
hypogonadism is the expression of the hypothalamic dysfunction also evidenced by
their hypotonia, hyperphagia, and intermittent temperature instability.
4.2.1.2 Acquired Origins

Traumatic brain injury: Traumatic brain injury (TBI) is an insult to the brain that
results in neurologic dysfunction. TBI can determine anterior pituitary insufficiency
and in particular gonadotropin deficiency may be found in 42% in the acute phase,
at the 12-month follow-up many of these patients spontaneously recovered repro-
ductive function. The final prevalence of hypogonadism is 7.7%.
Central nervous system diseases: Intracranial tumor is a common cause of
acquired hypogonadism in adolescence (e.g., craniopharyngiomas and pituitary
adenomas including prolactinoma). HH can result from the compression of pitu-
itary tissue/stalk or secondary to inhibition of GnRH secretion in the case of
prolactinoma or Cushing’s disease. Clinically, visual disturbance or headaches
may accompany pubertal arrest in these cases. Importantly, all patients with pitu-
itary tumors should have a complete evaluation of anterior and posterior pituitary
function.
In children, resultant hypogonadotropic hypogonadism can exist as a result
of the primary cerebral tumor or due to the therapeutic regimen needed to treat
the lesion (chemotherapy and radiotherapy). Gonadotropin deficiency and
delayed puberty are most likely in those who receive 40 Gy or more of radiation.
Gonadotropin deficiency may continue to evolve for many years after radiation,
with rates of total incidence ranging from 20 to 50%. Therefore, all children
who have CNS lesions should be monitored for gonadotropin deficiency and
signs of pubertal delay. Central hypogonadotropic hypogonadism can be caused
by previous central nervous system infection or autoimmune destruction of the
pituitary.
Functional hypothalamic amenorrhea: Functional hypothalamic amenorrhea
occurs when hypothalamic-pituitary-ovarian axis is suppressed due to an energy
deficit stemming from stress, weight loss, excessive exercise, or eating disorders
[6, 7]. So, it is commonly associated with eating disorders such as anorexia nervosa
and bulimia, and also occurs in elite female athletes. It is characterized by a low
estrogen state without other organic or structural disease. Patients with functional
amenorrhea may demonstrate the features of the female athlete triad, which con-
sists of insufficient caloric intake with or without an eating disorder, amenorrhea,
and low bone density or osteoporosis. Laboratory tests usually reveal low or low-
normal levels of serum follicle-stimulating hormone, luteinizing hormone, and
estradiol; however these levels can fluctuate, and the clinical context is the dis-
criminating factor. In these girls, suppression of GnRH secretion results in attenu-
ation of LH and FSH release, decreased estrogen production, and low circulating
leptin levels.
In addition, chronic, systemic illness can cause HH via deficits in nutritional
intake creating a negative energy balance or chronic inflammatory states resulting
from immunologic disorders (i.e., inflammatory bowel disease and celiac disease)
or psychological stress.
Drugs such as opiates and steroids can also suppress the HPG axis.
4.2.2 Hypergonadotropic Hypogonadism
Delayed onset of puberty or stalled pubertal development can also be caused by

gonadal defects that may first become evident in adolescence. In such cases, unre-
sponsive defective gonads lead to increased serum gonadotropin levels that charac-
terize hypergonadotropic hypogonadism [5].
Primary hypogonadism can be due to congenital origins such as chromosomal
abnormalities, syndrome, or genetic mutations, but it can also be acquired later in
childhood or adolescence due to autoimmunity or exposure to chemotherapy or
radiation (Table 4.1).
4.2.2.1 Congenital Origins

Turner syndrome: The most common cause of congenital primary hypogonadism is
sex chromosome aneuploidy as is present in Turner syndrome [8]. It occurs in
1:2500 live born females. Diagnosis is suggested by characteristic physical features,
including short stature, webbed neck, high palate, renal and cardiac malformations
and confirmed by karyotypic analysis showing a partial or complete absence of an
X chromosome or a chromosomal mosaicism. In adolescence, key diagnostic fea-
tures include short disproportionate stature and ovarian insufficiency resulting in
absent or incomplete puberty. In some instances, primary amenorrhea is the only
presenting symptom. While most TS patients will require pubertal induction, about
one-third of girls present with spontaneous initiation of puberty and 5% exhibit
menarche and 2% spontaneous pregnancy.
Although intrinsically normal, the ovaries in girls with TS undergo accelerated
atresia such that the timing of ovarian failure is variable and can occur anytime
between childhood and young adulthood. FSH levels may be very elevated in TS in
the first 2 years of life, revealing precocious gonadal insufficiency. Hypogonadism
in these patients not only affects puberty and reproductive capacity but also has
consequences on metabolic, hepatic, cardiovascular and bone health (density).
Gonadal dysgenesis: The second largest group of young women with primary
ovarian insufficiency has a 46, XX karyotype (46, XX gonadal dysgenesis). Some
of them have an autosomal recessive form of the disorder, and others have premuta-
tion for the fragile X syndrome.
Primary ovarian insufficiency: Primary ovarian insufficiency, a condition char-
acterized by follicle depletion or dysfunction leading to a continuum of impaired
ovarian function, is suggested by a concentration of follicle-stimulating hormone in
the menopausal range, confirmed on two occasions separated by 1 month, and diag-
nosed in patients younger than 40 years with amenorrhea or oligomenorrhea [9, 10].
Other terms, including premature ovarian failure, are used synonymously with pri-
mary ovarian insufficiency. Up to 1% of women may experience primary ovarian
insufficiency. More than 90% of cases unrelated to a syndrome are idiopathic, but
they can be attributed to radiation, chemotherapeutic agents, infections, tumors,
empty sella syndrome, or an autoimmune or infiltrative process.
Patients with primary ovarian insufficiency should be counseled about possible

infertility, because up to 10% of such patients may achieve temporary and unpre-
dictable remission.
There is evidence of genetic predisposition to primary ovarian insufficiency, and
patients without evidence of a syndrome should be tested for FMR1 gene mutation
[11].
X chromosome abnormalities: Other X chromosome abnormalities, including Xq
deletion and Triple X, can cause varying degrees of hypogonadism. The proximal
regions of both the p and the q arms of the X chromosomes are most critical for
maintenance of the germ cell compliment and also terminal deletions at the telo-
meric regions of these arms are associated with oocyte depletion. Deletion of these
regions is more likely to result in premature ovarian insufficiency after some period
of ovarian function rather than a complete loss of germ cells evident at the start of
the teenage years as is more commonly seen with the proximal deletions. Early
molecular studies have identified two regions of the long arm of the X chromosome
within the translocation breakpoints which were felt to harbor important ovarian
determinant genes. POF1 (Xq26–q28) contains several candidate genes (HS6ST2,
TDPF3, GPC3) and one known to be associated with POI, the Fragile Mental
Retardation 1 (FMR1) gene. POF2 (Xq13.3–q22) contains several candidate genes
for which one has been disrupted in POI.
Xq deletion can cause a phenotype similar to TS as well as isolated premature
ovarian failure. Deletions in the critical region, Xq13–q26, can also lead to prema-
ture ovarian failure.
Abnormalities in gonadotropin production or action: Mutations within the beta-
subunit of the gonadotropins, the gonadotropin receptors, or forms of resistance to
gonadotropins can all result in hypergonadotropic hypogonadism. Females with
mutations in the beta-subunit of FSH present with primary amenorrhea, delayed
puberty, and poorly developed secondary sexual characteristics; they have low FSH
levels, low estradiol levels, and high LH levels due to lack of feedback inhibition by
estradiol. In females, LH resistance results in normal puberty but subsequent amen-
orrhea, infertility, and elevated LH levels, demonstrating that ovulation requires LH
as well as FSH.
Galactosemia: Galactosemia results from a deficiency in galactose-1-phosphate
uridyltransferase (GALT). In females, the disease can result in hypergonadotropic
hypogonadism with varying degrees of primary and secondary amenorrhea and oli-
gomenorrhea. Ultrasound studies of the ovaries showed streak gonads in most
affected females, so the cause is premature ovarian failure, as demonstrated by ele-
vated levels of FSH, although the pathophysiology is not well understood.
4.2.2.2 Acquired Origins

The most important acquired origins include treatment for pediatric cancer (radia-
tion and chemotherapy) and autoimmune conditions.
Chemotherapy and radiation: Advances in the treatment of childhood cancer
(surgery, chemotherapy/radiotherapy) have improved survival rates and growing
numbers of adolescents are presenting with acquired forms of hypogonadism sec-

ondary to treatment of pediatric cancers. The type of treatment, dosage/exposure,
and age of treatment are important determinants of gonadotoxicity and patients
treated at a younger age typically have lower risk for long-term, deleterious repro-
ductive effects. In girls, the dose of intra-abdominal radiation needed to destroy
more than 50% of developing oocytes in less than 2 Gy. In the 70% of patients who
survive pediatric cancer, one in six female survivors develops primary ovarian fail-
ure and those who undergo spontaneous menarche have decreased ovarian reserve.
If chemotherapy (vincristina, l-asparaginase, methotrexate, 6-mercaptopurina) is
combined with total body radiation, the risk of developing premature ovarian fail-
ure is very high. Sporadic case of spontaneous recovery of ovarian function in
childhood cancer survivors has been reported; although most common in older chil-
dren and adults, recovery of ovarian function has occurred as long as 12 years post-
exposure to radiation and alkylating chemotherapy.
Autoimmune gonadal failure: The most common cause of premature ovarian
failure in adolescents with a 46, XX karyotype, for whom an abnormality has not
identified, is autoimmunity. Autoimmunity can lead to ovarian failure, especially
in those who have other types of autoimmune endocrinopathies. Autoimmune
polyglandular syndrome (APS) I and II have been associated with premature
ovarian failure at prevalence rates of 30–50%. APS I consists of a triad of hypo-
parathyroidism, mucocutaneous candidiasis, and adrenal insufficiency. The muta-
tion is within the AIRE gene. Patients with one autoimmunity disease should be
regularly screened for other endocrinopathies on routine basis.
4.3 Evaluation
If gonadal failure is congenital or starts before pubertal development (chronological

age <8 years), it generally manifests with pubertal delay and primary amenorrhea
[12]. So the clinical suspicion arises in peripubertal age when clinical signs of
pubertal development are lacking (Table 4.2 and Fig. 4.1).
Primary amenorrhea is defined as the failure to reach menarche. Evaluation
should be undertaken if there is no pubertal development by 13 years of age, if men-
arche has not occurred 5 years after initial breast development, or if the patient is
15 years or older (Figs. 4.1 and 4.2).
In these cases, clinical evaluation begins with a careful clinical history and physi-
cal examination (Table 4.2). Important elements on history include the parents’
pubertal timing because late menarche in the mother or delayed completion of adult
height in the father is strongly suggestive of CDGP. History should include attention
to any CNS insult, symptoms of chronic disease or history of cancer and treatments
with chemotherapy and/or radiotherapy.
Lack of sense of smell can be an important clue to the presence of Kallmann
syndrome.
Table 4.2 Findings in the History

evaluation of pubertal delay 1. Family history of delayed menarche or pubertal delay in
and amenorrhea the father
2. Chronic illness
3. Chemotherapy or radiation
4. Weight loss, excessive exercise, poor nutrition,
psychosocial stress, diets
5. Galactorrhea
6. Menarche and menstrual history
7. Illicit drug use
8. Medications
9. Sexual activity
10. Significant headache and vision changes
11. Vasomotor symptoms
Physical examination
1. Anthropometric measurements (weight and height)
2. Evaluation of growth chart
3. Body mass index (nutritional status)
4. Dysmorphic features (webbed neck, short stature, low
hairline)
5. Tanner staging for pubertal signs
6. Thyroid examination
7. Male pattern baldness, increased facial hair, acne
Laboratory testing
1. Complete blood count and metabolic panel abnormalities
2. Estradiol
3. FSH and LH
4. Free and total testosterone, DHEAS
5. Karyotype
6. Prolactin
7. Pregnancy test
8. Thyroid-stimulating hormone
Diagnostic imaging
1. Pelvic ultrasonography (presence of malformation of
uterus, ovaries volume and structure)
2. Magnetic resonance imaging of head or sella turcica
The physician should measure the patient’s height, weight, and body mass index,
and evaluate secondary sexual characteristics according to Tanner staging. Short
stature, dysmorphic features such as webbed neck or low hairline may suggest
Turner syndrome.
If gonadal failure starts after menarche, it determines secondary amenorrhea that
is defined as the cessation of previously regular menses for 6 months.
Breast development is an excellent marker for ovarian estrogen production. Thin
vaginal mucosa is suggestive of low estrogen. Patients should be asked about eating
and exercise patterns, change in weight, and previous menses (if any).
Neurological assessment should include evaluation of visual fields.
Gonadal failure may manifest with primary or secondary amenorrhea [13], so
differential diagnosis should include all the conditions that can lead to primary and
secondary amenorrhea (Figs.4.2 and 4.3).
Delayed puberty in girls

(no breast enlargment > 13 years)
Exclude family hystory of pubertal delay

and chronic illness
Pelvic ultrasound
Ovarian changes Prepubertal small ovaries
FSH and LH
Maturational delay
(more likely if patients is Low High
short for family)
Absent response to
GnRH test Ovarian failure
Gonadotropin deficiency, hypothalamic disturbance,

eating disorders, prolactinoma, extreme maturational delay
Fig. 4.1 Schematic algorithm for assessing adolescent females presenting with lack of pubertal
development
Clinical history and

physical examination
NO Presence of secondary sexual characteristics YES
Determination of FSH and LH Uterus present ?
NO YES
FSH and LH FSH > 20 mIU/ml

< 5 mIU/ml LH > 40 mIU/ml Karyotype, free/total Anatomic
testosterone abnormalities
Functional Turner syndrome,

amenorrhea, Primary ovarian insufficiency,
46 XX 46 XY
CDGP, Gonadal dysgenesis
primary HH
Mullerian Androgen
agenesis insensitivity
syndrome
Fig. 4.2 A diagnostic approach to primary amenorrhea

Clinical history and physical examination

Review medications/illicit drugs
Pregnancy test negative, check TSH and prolactin
Both normal
Normal prolactin, abnormal Normal TSH,
TSH levels abnormal prolactin levels
Progestogen No withdrawal bleed,

Challenge test Thyroid disease
check FSH and LH Prolactin < Prolactin >
100 ng/ml 100 ng/ml
Withdrawal Elevated Low

bleed FSH and LH FSH and LH
Consider other Perform MRI
causes to evaluate for
prolactinoma
Normogonadotropic Hypergonadotropic
hypogonadism hypogonadism
Perform MRI to exclude

pituitary tumor
Fig. 4.3 A diagnostic approach to secondary amenorrhea
4.4 Diagnostic Workup
The initial workup includes serum luteinizing hormone, follicle-stimulating hor-

mone, and estrogen levels.
Low gonadotropin levels suggest CDGP or pathologic hypogonadotropic hypo-
gonadism and can be further evaluated with GnRH stimulation test [14, 15]. In
contrast, elevated gonadotropins indicate primary gonadal failure. A bone age
radiograph is an essential component of the evaluation; in fact in CDGP it is gener-
ally retarded in respect to chronological age, while in hypo- and hypergonadotropic
hypogonadism it is correspondent to chronological age.
If the patient is short in stature, a karyotype analysis should be performed to
exclude Turner syndrome. A complete blood count and a comprehensive metabolic
panel may be useful if history or examination is suggestive of chronic disease.
Autoimmune panel or molecular genetic analysis may be indicated if other possible
causes have been excluded.
Pelvic ultrasonography can identify volume and anatomical abnormalities (streak
gonads) of the ovaries.
If a pituitary tumor is suspected or elevated levels of prolactin have been detected,
magnetic resonance imaging (MRI) may be indicated.
4.5 Treatment
In general, there are several goals for treating hypogonadism in adolescence: devel-
oping secondary sexual characteristics and growth as well as inducing gonadal
maturation for future fertility [16].
The initiation of estrogen therapy at an age concordant with normal endogenous
ovarian production (i.e., at least by ages 9–11 years) has always been considered
important for normal psychosocial development of the adolescent.
All patients with premature gonadal failure need estrogen therapy for initiation
and completion of pubertal progression and subsequently for the maintenance of a
multitude of health processes [5, 12]. Remodeling of bone is of utmost importance,
but other physiologic processes are dependent on normal estrogen status as well at
least through 50 years of age. The findings and concerns for long-term hormone
replacement of the Women’s Health Initiative do not apply to these or any other
patient prior to the age of 50 years and should not be used to prematurely stop their
hormone replacement.
Counseling is of utmost importance for these individuals and should cover
expectations.
Primary insufficiency can be corrected by hormone therapy according to the fol-
lowing schedule:
100 mcg of daily transdermal estradiol or 0.625 mg of daily conjugated equine
estrogen on days 1 through 26 of the menstrual cycle + 10 mg of cyclic medroxy-
progesterone acetate for 12 days (e.g., days 14 through 26) of the menstrual cycle.
This regimen should be administered until the average age of natural menopause
and is recommended to decrease the risk of ischemic heart disease and
osteoporosis.
Combined oral contraceptives (OCs) deliver higher concentrations of estrogen
and progesterone than necessary for hormone therapy, may confer thromboembolic
risk, and may theoretically be ineffective at suppressing follicle-stimulating hor-
mone for contraceptive purposes in the population: thus a barrier method or intra-
uterine device is appropriate in sexually active patients.
For optimal bone health, patients with primary ovarian insufficiency need a sup-
plement of calcium (e.g., 1200 mg daily) and vitamin D (e.g., 800 IU daily).
Treatment of functional hypothalamic amenorrhea involves nutritional rehabili-
tation as well as reduction in stress and exercise levels. Menses typically return after
correction of the underlying nutritional deficit. The patient should take calcium and
vitamin D supplements. Estrogen replacement without nutritional rehabilitation
does not reverse the bone loss. Combined oral contraceptive pills will restore men-
ses, but will not correct bone density. Leptin administration has been reported to
restore pulsatility of gonadotropin-releasing hormone and ovulation in these
patients, but its effect on bone health is unknown.
The physical development of puberty is accompanied by psychosocial and emo-
tional changes, so disrupted puberty can carry a psychological burden as well as
anxiety and depression. Treatment inducing growth and development of secondary

sexual characteristics may be helpful in alleviating some of the distress hypogo-
nadal adolescents experience related to their lack of development. Frank discussion
of patients’ concerns, anticipatory guidance, and emotional support should be an
integral part of their care.
Therefore, a holistic, collaborative approach including psychological counseling
is a key component of managing hypogonadism in adolescence.
4.5.1 Transition of Adolescents to Adult Care
The transition from pediatric to adult care is a challenge for patients with chronic
endocrine conditions with different disorders having condition-specific needs. Too
often, the transition process is characterized by cracks and gaps in care as reported
for patients with TS. Such disjointed care can negatively impact health and quality
of life for adolescents with hypogonadism as periods without treatment result in
decreased sexual function, diminished energy, and poor bone density. Special tran-
sition clinics where pediatric and adult endocrinologist work together are increas-
ingly being created to bridge care and promote continuity and adherence to treatment
[17, 18].
Conclusions
Hypogonadism in adolescence results from a variety of causes including con-
genital and acquired forms. Early diagnosis is important for initiating treatment
to develop secondary sexual characteristics and growth as well as for inducing
gonadal maturation for future fertility.
Furthermore, early treatment may help to minimize some of the psychosocial
impacts of hypogonadism on adolescents.
References
1. Grumbach MM, Styne DM. Puberty: ontogeny, neuroendocrinology, physiology and disor-
ders. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PP, editors. Williams’ textbook of
endocrinology. 9th ed. Philadelphia: Saunders; 1998. p. 1509–625.
2. Kuiri-Hänninen T, Sankilampi U, Dunkel L. Activation of the hypothalamic-pituitary-gonadal
axis in infancy: minipuberty. Horm Res Paediatr. 2014;82(2):73–80.
3. McLean M, Davis AJ, Reindollar RH. Abnormalities of female pubertal development. In:
De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C,
Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A, editors. Endotext.
South Dartmouth: MDText.com; 2000–2015.
4. Dwyer AA, Phan-Hug F, Hauschild M, Elowe-Gruau E, Pitteloud N. Hypogonadism in adoles-
cence. Eur J Endocrinol. 2015;173(1):R15–24.
5. Viswanathan V, Eugster EA. Etiology and treatment of hypogonadism in adolescents. Pediatr
Clin N Am. 2011;58(5):1181–200.
6. Meczekalski B, Katulski K, Czyzyk A, Podfigurna-Stopa A, Maciejewska-Jeske M. Functional
hypothalamic amenorrhea and its influence on women’s health. J Endocrinol Invest.
2014;37(11):1049–56.
7. Gordon CM. Clinical practice. Functional hypothalamic amenorrhea. N Engl J Med.

2010;363(4):365–71.
8. Sybert VP, McCauley E. Turner’s syndrome. N Engl J Med. 2004;351(12):1227–38.
9. Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med. 2009;360(6):606–14.
10. Fenton AJ. Premature ovarian insufficiency: pathogenesis and management. J Midlife Health.
2015;6(4):147–53.
11. Chapman C, Cree L, Shelling AN. The genetics of premature ovarian failure: current perspec-
tives. Int J Womens Health. 2015;7:799–810.
12. Palmert MR, Dunkel L. Clinical practice. Delayed puberty. N Engl J Med. 2012;366(5):443–53.
13. Klein DA, Poth MA. Amenorrhea: an approach to diagnosis and management. Am Fam
Physician. 2013;87(11):781–8.
14. Odink RJ, Schoemaker J, Schoute E, Herdes E, Delemarre-van de Waal HA. Predictive value
of serum follicle-stimulating hormone levels in the differentiation between hypogonadotropic
hypogonadism and constitutional delay of puberty. Horm Res. 1998;49(6):279–87.
15. Harrington J, Palmert MR. Clinical review: distinguishing constitutional delay of growth and
puberty from isolated hypogonadotropic hypogonadism: critical appraisal of available diag-
nostic tests. J Clin Endocrinol Metab. 2012;97(9):3056–67.
16. Brook CG. Treatment of late puberty. Horm Res. 1999;51:101–3.
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healthcare: a systematic review. Arch Dis Child. 2011;96(6):548–53.
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sition period. Pediatr Endocrinol Rev. 2009;6(Suppl 4):519–22.
Dysmenorrhea
5
Abbreviations
ACOG American College of Obstetricians and Gynecologists

ESR Erythrocyte sedimentation rate
FDA Food and Drug Administration
Hz Hertz
IRCCS Istituto di Ricovero e Cura a Carattere Scientifico
LT Leukotriene
NSAID Non-steroidal anti-inflammatory drug
OC Oral contraceptive
OHVIRA Obstructed hemi vagina ipsilateral renal agenesis
PgE2 Prostaglandin E2
PgF2α Prostaglandin F2α
PG Prostaglandin
PID Pelvic inflammatory disease
STD Sexually transmitted disease
TENS Transcutaneous electric nerve stimulation
VAS Visual Analogue Score
VMS Verbal Multidimensional Scoring System
G. Tridenti, M.D. (*) • C. Vezzani, M.D.

Department of Obstetrics and Gynaecology, Santa Maria Nuova Hospital—IRCCS,
iale Risorgimento 80, 42123 Reggio Emilia, Italy

78 G. Tridenti and C. Vezzani
The term dysmenorrhea comes from the three ancient Greek words: δυς (difficult),
μην (month), ρεω (flow), and its literal meaning is “difficult menstrual flow” [1, 2].
Dysmenorrheic women have a significantly reduced quality of life, poorer mood,
and sleep quality during menses in comparison with non-dysmenorrheic women.
Menstrual pain affects many aspects of life, such as family relationships, friend-
ships, school/work performances, social/recreational activities, and physical activi-
ties as well [3]. Being reported by 15–85% women, dysmenorrhea is the most
frequent genital complaints in teenage and it is the main cause of recurrent short-
term absenteeism from school or work. Usually, appearing within 6–12 months
after menarche, it is less frequent during the first 2–3 postmenarchal years, when
menstrual cycles are mostly anovulatory, while its incidence grows in mid- and late
adolescence, with the establishing of ovulatory cycles. Dysmenorrhea is very often
misdiagnosed, untreated, or undertreated, with high percentages of self-medication,
often in nontherapeutic dose to achieve a quick relief of pain [4, 5]. Sixty to seventy
percent adolescents report painful menses; 15% interrupt daily activities because of
pain, with school absenteeism in 14–52% of cases, with a six-fold higher incidence
if a family history of dysmenorrhea is present [6, 7]. Dysmenorrhea may decrease
after giving birth or with advancing age [8]. The perception of pain may be the
result of strictly individual factors, such as attitude towards menses, pain threshold,
and mood [4].
The typical clinical picture of primary dysmenorrhea includes painful lower
abdominal cramps:
–– Requiring medication or limiting normal activity

–– Starting with menstruation or within a few hours before or after its onset
–– Lasting no more than 24–48 h
–– Strictly correlated with ovulatory cycles and duration and amount of menses [9]
On the contrary, in premenstrual syndrome symptoms start before menstruation,

occur, and resolve shortly after the onset of menstrual bleeding [10].
Commonest risk factors of dysmenorrhea are:
• Family history • Frequent life changes
• Young age • Few social supports
• Precocious menarche • Stressful close relationships
• Heavy and prolonged menstrual flows • Low socioeconomic level
• Nulliparity • Low fish intake
• Smoking and exposure to environmental • Poor physical activity
tobacco smoking • Underweight and overweight
• Marked uterine retroversion
• Low intake of polyunsaturated fatty acids
• Vitamin D deficiency
Balbi et al. [11], Dei and Bruni [12]

5 Dysmenorrhea 79
Two different main clinical pictures exist among affected teenagers:
• Primary Dysmenorrhea: at postmenarchal onset, it accounts for the 90% of cases

in teenagers and typically comprises recurrent abdominal painful cramps occur-
ring with menses without any identifiable pelvic pathology.
• Secondary Dysmenorrhea, in 10% adolescent cases, at late onset depending on
the underlying disease, with menstrual pains associated with well-defined pelvic
pathologies, such as:
– Endometriosis – Interstitial cystitis
– Mullerian obstructive anomalies – Adenomyosis
– PID – Pedunculate submucous myomas
– STDs – Endometrial polyps
– Early pregnancy complications – Pelvic adhesions
– Cervical stenosis – Bowel inflammatory diseases
– Ovarian cysts and dermoids – Pelvic tuberculosis
– Sequelae of genital mutilations – Large ovarian cysts
Dei and Bruni [12], Harel [13], Sanfilippo, and Erb [14]
Secondary dysmenorrhea may be accompanied by other gynecological symp-
toms, such as intermenstrual bleeding and menorrhagia; moreover, the timing and
intensity of pain during the menstrual cycle may be constant or diffuse, and not
necessarily associated with menses [4].
Affecting 8–10% women of reproductive age, endometriosis, that is endometrial
tissue in extrauterine locations, is the most frequent etiology of secondary dysmen-
orrhea and it is associated with obstructive genital anomalies in 11% cases [14, 15].
Another possible cause of secondary dysmenorrhea is adenomyosis, that is endome-
trial tissue within the myometrium, recently detected also in adolescents and more
frequently than previously expected [16].
All Mullerian anomalies may give rise to secondary dysmenorrhea because of
altered vascularity. Nevertheless, heavier and worsening clinical pictures may occur
in obstructed uterine and/or vaginal anomalies, such as noncommunicating func-
tioning rudimentary uterine horn and obstructed hemivagina. Most cases are part of
complex asymmetrical uro-genital malformations with duplex uteri and vaginae
with unilateral renal agenesis [12].
The pathophysiology of primary dysmenorrhea shows different steps, with a
major role of defined inflammatory lesions occurring in the menstruating womb:
• Increase of ω-6 fatty acids (mainly arachidonic acid) in endometrial cell mem-
brane after ovulation and their release with premenstrual progesterone with-
drawal which activates lysosomal phospholipase.
• ω-3 fatty acids/ω-6 fatty acids ratio may play a role in the release of algogenic
factors.
• Activation of prostaglandins (PGs) and leukotrienes (LTs) cascade in the uterine
wall, with subsequent inflammation giving rise to cramps and systemic symptoms.
• Myometrial contractions, then ischemia and pain in the uterine muscle [17].
• Higher vasopressin and low nitric oxide blood levels may induce vasoconstric-
tion and myometrial contractions [18, 19].
• Uterine flexion may play a pathogenetic role in dysmenorrhea: if the best condi-
tion is uterine body and cervix on the same axis, with an angle of 180° + 30°,
greater or lesser angles could impede menstruation with stronger myometrial
contractions and pains: marked anteflexion and retroflexion both may rise men-
strual pains [20].
Up to now, the overproduction of uterine prostaglandins is the most widely

accepted explanation for primary dysmenorrhea. The severity of menstrual pain and
associated symptoms is directly proportional to the amount of prostaglandins
released, and their production is strictly connected to the endometrial exposure to
luteal phase progesterone and therefore to ovulation. Among all prostaglandins,
PgE2 and PgF2α are mainly involved in the pathogenesis of dysmenorrhea. While the
former may result in either myometrial contraction or relaxation, the latter elicits
both strong vasoconstriction of uterine blood vessels and myometrial contractions,
lowering also pain threshold by sensitizing nerve endings to pain. In the pathogen-
esis of dysmenorrhea, a more and more relevant role of central factors was shown,
even if their relationship with peripheral factors has still to be fully clarified.
Unknown genetic or environmental factors and congenital variants in the pain pro-
cessing of the central nervous system may predispose dysmenorrheic women to a
greater pain perception, being mainly hypersensitive to deep muscle pain [4].
Dysmenorrheic women displayed a shift in the balance between pro-inflammatory
cytokines and anti-inflammatory transforming growth factor-β, with up-regulation
of genes coding for cytokines and down-regulation of the ones coding for trans-
forming growth factor-β; therefore in dysmenorrheic women, the inflammatory
response is different even without pain, with distorted hormonal and cytokine pro-
files [21]. Recurrent monthly dysmenorrhea may lead to the development of a cen-
tral sensitivity to pain, with an abnormal augmentation of pain perception by
mechanisms within the central nervous system [22]. Dysmenorrheic women are
supposed to have central changes which persist beyond menses being possibly
induced by the recurrent nociceptive stimuli into the central nervous system.
Primary dysmenorrhea may therefore raise the risk for the development of other
painful diseases later in life [23].
Signs and symptoms of primary dysmenorrhea are:
• Cramps • Loss of appetite • Diarrhea
• Nausea • Weakness • Facial blemishes
• Vomiting • Headache • Abdominal pains
• Bloating • Backache • Dizziness
• Flushing • Depression
• Sleeplessness • Irritability
• General aching • Nervousness
• Leg aches
5 Dysmenorrhea 81
The relationship between sleep and pain may be bidirectional, with pain disrupt-
ing sleep and disrupted sleep heightening pain perception [4].
Secondary dysmenorrhea more often shows
• Chronic pelvic pains

• Mid-cycle pains
• Dyspareunia
• Metrorrhagia
• Harel [13]
The main diagnostic symptom of primary dysmenorrhea is a colicky suprapubic

abdominal pain, occurring as follows:
• Along the lower abdomen midline

• Also described as a “dull” pain in both lower abdominal quadrants, lumbar areas,
and thighs
• Appearing with the onset of ovulatory cycles
• Starting just few hours before or after the onset of menses
• With frequent associated symptoms such as diarrhea, nausea, vomiting, weak-
ness, lightheadedness, headache, dizziness, lipothymia, fever, etc.
Associated symptoms peak with maximum blood flow and usually last less than
1 day. Pains may last 2–3 days at most and are quite similar in every menstrual
period [5]. Being a subjective symptom, the quantification of dysmenorrhea is dif-
ficult. Its intensity may be:
• Mild, not disturbing daily activities nor requiring painkillers

• Moderate, slightly interfering with daily routines but manageable with pain
killers
• Severe, markedly preventing daily life activities [24]
To measure and to grade dysmenorrhea, the two most common tools currently in
use rely upon girls’ self-reporting, which is unavoidably subjective and inaccurate:
(a) A verbal multidimensional scoring system, such as the “Menstrual Distress

Questionnaire” and the “Menstrual Symptom Questionnaire,” both considering
the impacts of pain on daily activities, systemic symptoms, and analgesic
requirements (Table 5.1);
(b) A linear visual analogue scale (VAS): a 10 cm line drawn on a sheet of paper,
representing a continuum of severity of pain from “no pain at all” at one extreme
till “unbearable pain” at the opposite one. The patient is asked to rate pain with
a mark on the line and the result is achieved by measuring the distance from
zero to the mark (Fig. 5.1).
Table 5.1 Verbal multidimensional scoring system (VMS)

Systemic
Grade Working ability symptoms Analgesia
Grade 0: Non-painful menstruation Unaffected None Not required
Unaffected daily activity
Grade 1: Painful menstruation seldom Rarely affected None Rarely required
inhibiting the woman’s normal
activity
Analgesics seldom required. Mild
pain
Grade 2: Daily activity affected. Moderate Moderately Few Moderately
pain affected required
Analgesics required giving relief
Absence from school/work is
unusual
Grade 3: Activity clearly inhibited. Severe Clearly affected Apparent Poor effect
pain
Poor effect of analgesics. Vegetative
symptoms (headache, tiredness,
nausea, vomiting, diarrhea)
Gamit KS, et al. “International Journal of Medical Science and Public Health,” (2014)
Visual Analogue Scale

Choose a Number from 0 to 10 That best Describes Your Pain
No Distressing Unbearable
Pain pain Pain
0 1 2 3 4 5 6 7 8 9 10
ASK PATIENTS ABOUT THEIR PAIN
INTENSITY-LOCATION-ONSET-DURATION-VARIATION-QUALITY
“Faces” Pain Rating Scale
0 1 2 3 4 5
NO HURT HURTS HURTS HURTS HURTS HURTS
LITTLE BIT LITTLE MORE EVEN MORE WHOLE LOT WORST
Fig. 5.1 Linear Visual Analogue Scale (VAS) (www.researchgate.net/publication/259499877)
Both tools lack validation and cannot be trustfully employed in teens [8].
Taking into account the onset of dysmenorrhea, different clinical pictures may be
identified:
5 Dysmenorrhea 83
• Early onset dysmenorrhea, appearing within 6 postmenarchal months or in

clearly non-ovulatory patients, it is very likely due to an underlying obstructive
genital anomaly, and mainly Wunderlich/OHVIRA syndrome (uterus didelphys
with obstructed hemivagina and ipsilateral renal agenesis).
• Late onset dysmenorrhea, arising after some years of painless periods, highly
suggests secondary dysmenorrhea.
• Sudden onset dysmenorrhea, suddenly arising in non-symptomatic or oligo-
symptomatic patients, makes PID and early pregnancy complications (miscar-
riage or ectopic pregnancy) suspected [25].
Clinical approach to dysmenorrheic patients must follow good medical practice

recommendations:
MEDICAL HISTORY, properly focused on menstruation, allows for differential
diagnosis between primary and secondary dysmenorrhea by considering:
– Age at menarche – Associated symptoms
– Length and regularity of cycles – Chronology of associated symptoms related to
menses
– Dates of the last two menses – Severity and duration of associated symptoms
– Duration and amount of flows – Progression of associated symptoms over time
– Type, location, and radiation of pain – Time between menarche and onset of symptoms
– Worsening of pain over time – Degree of patient’s disability
– Gastrointestinal and urinary – Lifestyle (food, smoking, physical activity)
functions
Bettendorf et al. [26]
Other items to be considered in medical history:
• Sexual activity, dyspareunia, contraception

• Past obstetric and gynecologic events, and mainly STDs, PID, pelvic surgery,
infertility
• Other medical problems
• Family history of endometriosis in first degree relatives
• All previous treatments, ways of administration, and outcomes
• Other ongoing medical treatments
• Dei and Bruni [12], Harel [13]
• Meal skipping
• Less sleep
• Higher sugar intake
are other important risk factors for the occurrence of dysmenorrhea [6].
PHYSICAL EXAMINATION must follow several steps.
• Abdominal evaluation is always indicated to detect palpable masses.

• Inspection of external genitalia is mandatory in young girls to rule out abnormal
hymens.
• Pelvic exam (vaginal or rectal), not indicated in virgins with mild to moderate
dysmenorrhea, must be performed:
–– In sexually active girls
–– If organic diseases or genital anomalies are suspected
–– With no response to conventional treatments of primary dysmenorrhea
LABORATORY TESTING OR IMAGING, not required to diagnose primary dys-

menorrhea, are advisable if secondary dysmenorrhea is suspected. Laboratory test-
ing are not resolving, and they may be useful if a pelvic inflammatory disease is
suspected, with a slight increase of both erythrocyte sedimentation rate (ESR) and
protein C reactive and possible positive cervical swabs [12].
• Ultrasonography, first-step diagnostic tool to image the pelvis, including also the
assessment of number and location of kidneys in girls, is widely performed even
if no evidence exists about its routine application in primary dysmenorrhea. On
the contrary, pelvic ultrasonography is mandatory:
–– In the diagnostic workup of secondary dysmenorrhea
–– With no response to first-line treatments
–– With an abnormal, impossible, or unsatisfactory pelvic exam
The transabdominal approach is usually preferred in young patients.
Nevertheless, it must be borne in mind that ultrasonography can never replace
physical exam.
• Magnetic resonance imaging is unnecessary in the diagnosis of primary dysmen-
orrhea while it may be useful to detect adenomyosis, Mullerian anomalies, and-
bladder lesions [27].
• Hysteroscopy and sonohysterography can highlight congenital anomalies of the
uterine cavity and endometrial polyps and submucous myomas as well.
• Laparoscopy is still the gold standard in the diagnostic workup of secondary
dysmenorrhea due to endometriosis, PID, and pelvic adhesions. It must be
performed
–– With highly suspected organic pathologies
–– With failed first-line treatments.
It is not to be delayed in refractory to therapy teens if endometriosis is suspected;

biopsies of lesions are mandatory if endometriosis is diagnosed [28].
5.1 Treatments
Different therapeutic approaches to dysmenorrhea exist, and they may be grouped

as follows:
• Non-medical options
• Medical options, both hormonal and nonhormonal ones
• Surgical options
• Complementary and alternative medicine
5 Dysmenorrhea 85
Treatments of dysmenorrhea may also be classified into

Conventional therapies:
Non-steroidal anti-inflammatory drugs (NSAIDs)
Oral contraceptives (OCs)
Surgery
Nonconventional therapies:
Behavioral treatments
Physical exercise
Manipulation of the spine
Reflexotherapy
Heat therapy
TENS
Acupuncture
Magnetotherapy
Alternative medicine
Non-medical treatments include:
• Diet: by lowering animal fats intake in favor of ω-3 fatty acids provided food,
such as fish [12].
• Physical exercise may act on dysmenorrhea by enhancing β-endorphins release
and by bettering pelvic blood flows. The results are controversial but it must
always be advised as a first-step therapy.
• Transcutaneous electrical nerve stimulation (TENS) may be distinguished in
–– High frequency TENS (50–120 Hz): with low effect, it is more effective than
placebo
–– Low frequency TENS: not effective at all in fact
Self-regulated by the patient, it is a non-medicinal-no-risk procedure acting by acti-

vation of the large-diameter Aβ proprioceptive nerve fibers of the skin with no acti-
vation of both finer Αδ fibers and pain C fibers. TENS effectiveness relies on the rise
of pain threshold, preventing pelvic painful stimuli to reach the spinal cord.
Furthermore, it enhances β-endorphins secretion and it betters uterine blood flow.
Positive effects, if present, are perceivable within few minutes from the application
of the device [13, 29, 30].
• Acupuncture: well tolerated without side effects procedure, it has been approved
by FDA. It significantly lowers pain in mild-to-severe dysmenorrhea, with a long-
acting effect. More expensive than NSAIDs and OCs, it may be recommended
when first-line treatments are rejected or contraindicated. To establish proper rec-
ommendations and administration, further data are required [29, 31, 32].
• Manipulation of the spine: as some Authors suggest, the rationale of this proce-
dure relies upon the existing close relationship of pelvic sympathetic and para-
sympathetic nerve pathways with spine segments T10-2L and S2–S4. Possible
vertebral mechanical dysfunctions, with lowered mobility of the spine, could
alter sympathetic pathways regulating blood supply in pelvic organs, with subse-
quent vasoconstriction and dysmenorrhea. Vertebral manipulation could improve
spine mobility and increase pelvic blood supply by action on vessels innervation,
thus bettering dysmenorrhea. According to Cochrane Library, the efficacy of this

procedure has no evidence [33].
• Behavioral treatments, targeted to enhance central control of pain, include:
–– Relaxation exercises
–– Biofeedback
–– Counseling about management of pain
Their effectiveness is low, few data are available, the evidence is poor; therefore,
they are not recommended by Cochrane Library [34].
• Topical heat, very likely the most traditional treatment of dysmenorrhea, can be
supplied in different modalities:
–– Hot patches
–– Hot water bottle
–– Adhesive patches generating chemical heat.
Even if evidence is poor, their effectiveness is well known and it should be greater
than Acetaminophen and equal to Ibuprofen [13].
• Topical magnetic devices, about which poor evidence is reported, are static mag-
nets to be applied to the skin under the underwear.
• Reflexotherapy, with no evidence, like the above reported device, is mentioned
for completeness and consists of two procedures:
–– Application of a seed to an ear by a plaster, following the belief the ear hosts
trigger points connected with all body parts
–– Stimulation of the hands and mainly of the feet, which both should carry
reflexion areas connected to other body organs. Putting pressure on specific
trigger points should release energy activating the healing process [35, 36].
For the above-mentioned treatments, no evidence is reported [37].

The large variability in the reported outcomes of the various non-pharmacologic
approaches suggests the efficacy of such methods to be personal, differing from one
patient to the other [4].
Nonhormonal medical treatments display:
• Over-the-counter medications (acetaminophen): they increase the pain threshold

but their effectiveness is not assessed conclusively.
• Non-steroidal anti-inflammatory drugs (NSAIDs), classified as prostaglandin syn-
thetase inhibitors, are almost certainly effective by suppressing the endometrial
prostaglandin synthesis. They are the first-line medical treatment of dysmenorrhea
to be taken at the very onset of bleeding and/or associated symptoms. Naproxen
sodium, zomepirac sodium, mefenamic acid, ketoprofen, ibuprofen, and diclofe-
nac showed to be comparably effective on menstrual pain [38]. NSAIDs, mainly
Diclofenac, are effective in restoring both pain-related reduction in physical activi-
ties and sleep disturbances in dysmenorrheic women. NSAIDs effects are mostly
tolerable and gastrointestinal safety issues are generally less worrisome in acute
5 Dysmenorrhea 87
Table 5.2 Properties and side effects of most prescribed NSAIDs in dysmenorrhea
Peak blood Half-life
Active principle levels (h) Other effects
Acetosal 1 h 2–3 Increased menstrual flow
Ibuprofen 40′ 2–4 Unchanged menstrual flow
Ketoprofen 1–2 h 2 Photosensitizer, increased menstrual
flow
Naproxen 1 h 14 Increased menstrual flow
Indomethacin 2 h 2,5 Heavier gastric side effects
Sulindac 2 h 1
Diclofenac 2–3 h 1–2 Increased menstrual flow
Etodolac 1 h 7
Mefenamic acid 2–4 h 3–4 Inhibits LTs and synthesized PGs
Meclofenamate 1–2 h 2 Decreased menstrual flow
Piroxicam 2–4 h 45–50 Heavier gastric side effects
Piroxicam + β-cyclodextrin 30–60′ 45–50
Nimesulide 2 h 3 Decreased menstrual flow,
hepatotoxicity
Dei and Bruni [12]
administration than in chronic one [4]. Usually, a 2–3 days treatment is needed.
Maximum dosing is recommended, with twice the regular dose initial loading fol-
lowed by the usual dosage divided during the day. If the treatment is ineffective, a
different preparation is advisable even if the various NSAIDs formulations have
comparable efficacy on dysmenorrhea. Pain relief is achieved in 64–100% cases.
In non-responding women (15% of the whole), oral contraceptives may be offered
as a second-line treatment [34] (Table 5.2).
• Cox-2 inhibitors (Colecoxib) are advisable in patients reporting peptic ulcer or

intolerance to NSAIDs. According to FDA, they may be prescribed to over 18
patients.
• Transdermal glyceryl trinitrate relaxes the myometrium but it is less effective
than diclofenac.
Hormonal medical treatments are:
• Combined oral contraceptives (OCs), which are effective on dysmenorrhea and

safe in teenage, display also useful health benefits such as alleviation of acne and
protection against unintended pregnancies. This is the reason why OCs are the
first-line option in sexually active dysmenorrheic girls. In all patients, they may
be considered if a 6-month NSAIDs therapy is ineffective to be initiated while
continuing with NSAIDs and preferring extended regimens [39]. Their action on
dysmenorrhea is performed by:
–– Limiting endometrial growth and thickness.
–– Lowering PGs, LTs, and cyclooxygenase 2 blood levels.
–– Inhibiting ovulation and progesterone secretion, thereby reducing volume of

menstrual fluid, prostaglandins synthesis, and dysmenorrhea [39]. Very likely
OCs also lower blood pressure of uterine vessels. If symptoms persist during
the 7 days pill-free interval, an extended, interval-free, 3 months treatment is
advisable because of its high effectiveness on associated symptoms. If no pain
relief occurs with a 3–6 months OCs treatment, secondary dysmenorrhea
must be suspected and laparoscopy is recommended to diagnose and treat
possible endometriosis [13].
• Progestin only pill can decrease the amount of menstrual bleeding lowering
also abdominal cramps but further studies in dysmenorrheic patients are
requested [13].
• Depot medroxyprogesterone acetate (map) contraceptive is an efficacious, long-
acting, progestin-only, injecting contraceptive of which either intramuscular and
subcutaneous preparations are available (the latter is unavailable in Italy), both to
be administered once every 12 weeks. It can mitigate dysmenorrhea but in ado-
lescents concerns exist about possible side effects on bone mass density, mainly
after a 2-years long treatment. It is not a first-choice option in teenage. (www.
fda.gov/medwatch/SAFETY/DepoProveraLabel.pdf)
• Levonorgestrel-releasing intrauterine system can lower both menstrual blood
flow and pains. Even if concerns existed about its insertion in nulliparous and
adolescents, nowadays its administration in both of them is approved by
ACOG. Further opportunities in teenage are displayed by the launching on the
market of Jaydess. The copper intrauterine device was shown not to act on dys-
menorrhea [40, 41].
• Etonogestrel subdermal implant can better dysmenorrhea while in use. Its effec-
tiveness has been verified but further studies in adolescents are needed [42].
• Combined estrogen and progestin transdermal patch may mitigate the symptoms
but available data are controversial. Further studies are required before it may be
recommended as a treatment of dysmenorrhea [43].
• Combined estrogen and progestins vaginal ring was verified to be an effective
treatment of dysmenorrhea. An extended 84 days regimen is possible. After a
6 months administration, a significant bettering of the clinical picture was
seen [44].
• GnRH agonists showed to be effective for both primary dysmenorrhea and endo-
metriosis. Nevertheless, they are not advisable in under 16 adolescents because
of concern about bone demineralization, verified after a 6 months administration.
In longer-lasting treatments, an estroprogestin “add back” therapy is recom-
mended to prevent bone loss [45].
Even taking into account differences among various formulations and ways of
administration, NSAIDs and oral combined contraceptives (OCs) are first-line treat-
ments of dysmenorrhea.
5 Dysmenorrhea 89
5.2 Surgical Treatment
If dysmenorrhea is resistant to a 6 months NSAIDs treatment followed by a 6

months COC therapy, both diagnostic and therapeutic surgery is advisable.
Different surgical approaches are available:
• Laparoscopy is still the gold standard to diagnose and treat endometriosis, of

which the prevalence in adolescents is unclear but it is much more frequent than
supposed in the past.
According to various experiences, endometriosis was detected in:
62% girls undergoing laparoscopy because of pain.
75% girls with chronic pelvic pains resistant to treatment.
70% girls with dysmenorrhea.
49% girls with chronic pelvic pains not necessarily resistant to treatment [46].
Because of hesitation in performing laparoscopy in very young people, in
aged under 20 the diagnosis is often delayed with 10 years average delay
between early symptoms and diagnosis; therefore, serious damages and
impairment of future fertility are possible [47, 48]. Adolescents mostly show
minimal-to-mild endometriosis, but the disease may rapidly progress to more
severe stages, not correlated with symptoms. Even seldomly, stage III or IV
endometriosis with endometriomas were detected in teenagers too [49]. To
prevent long-term sequelae in adolescents, early diagnosis and treatment of
endometriosis are mandatory to be necessarily performed in the same surgical
setting [50]. In teenage, the recurrence risk is quite high (>20% at 2 years,
40–50% at 5 years); therefore, affected adolescents deserve close follow-up
for recurrences [49, 51]. Laparoscopy is also the gold standard to diagnose
and remove a noncommunicating functioning rudimentary horn, which may
give rise to nonrespondent worsening dysmenorrhea [52].
• Laparoscopic uterosacral nerve ablation does not lower dysmenorrhea, while it
carries risks for complications.
• Presacral neurectomy is the total transection of presacral nerves and it showed
good effectiveness in pain relief but complications are possible and evidence is
uncertain.
Drainage of a hemihematocolps with transvaginal removal of an obstructing

vaginal septum is the fully resolving surgical treatment of worsening secondary
dysmenorrhea in patient affected by duplex uteri and vaginae with lonely kidney
and obstructed hemivagina (ipsilateral to the renal agenesis) with hemihematocol-
pos frequently misdiagnosed as a pelvic mass. In 78% cases, a didelphic uterus was
found (Wunderlich/OHVIRA syndrome), while the remaining 22% showed a fully
septate uterus. Such complex malformations show an early onset worsening dys-
menorrhea when hemihematolpos occurs. The “gold standard” resolving treatment
Fig. 5.2 Wunderlich/
OHVIRA syndrome
is transvaginal drainage of the retained blood and ricanalization of the genital tract
by full removal of the vaginal septum. For completeness, didelphic uterus with uni-
lateral renal agenesis and ipsilateral Garter’s duct cyst (Herlyn-Werner Syndrome)
is to be mentioned, even if very rare. An obstructive genital anomaly must always
be suspected in an early onset non-respondent dysmenorrhea in adolescents. Early
diagnosis and surgical treatment are mandatory to preserve fertility [53, 54]
(Figs. 5.2 and 5.3).
• Hysterectomy is obviously not advisable in girls as a treatment of dysmenorrhea

while it may be considered in parous dysmenorrheic women not seeking for
further pregnancies and with an underlying uterine disease [55].
5.3 Complementary and Alternative Medicine
Such a definition groups different therapeutic proposals that are out of the conven-
tional medical system. Considered by many people as a “natural” remedy of dys-
menorrhea and equalized by the same lack of evidence according to Cochrane
Library, these treatments suppose primary dysmenorrhea to be due to a poor
assumption of fruits, eggs, and fish [37, 56–58].
5 Dysmenorrhea 91
Fig. 5.3 Septate uterus with

obstructed hemivagina and
ipsilateral renal agenesis
These therapies number:
• Vitamin B1, 100 mg daily 60 days long, with a verified bettering of the clinical
picture of which the mechanism of action is unknown. Moderate evidence of
lowered pain threshold and cramps was detected. Before prescribing Vitamin B1,
adequate dietary intake of vitamins is to be checked.
• Vitamin E, 500 mg a day, from 2 days before till 3 days after the onset of menses.
It acts by inhibiting protein kinase C, a membrane arachidonic acid release. It
significantly betters symptoms but evidences are low.
• Vitamin B6, 200 mg a day, may lower symptoms but further studies are needed.
• Fish oil, from salmon, tuna fish, halibut may be effective on dysmenorrhea. It
contains ω-3 polyunsaturated fatty acids (linolenic, eicosapentenoic, docosahex-
enoic acids) which, if dietary supplemented, may lessen dysmenorrhea by com-
petition with membrane ω-6 fatty acids, released during menses and subsequently
metabolized to prostaglandins. A dosage of 2.5 g daily may better symptoms but
no evidence exists and further studies are required. Nausea, acne, dyspepsia, and
fish flavor are possible side effects.
• Magnesium, 500 mg daily, showed to be more effective than placebo but further
studies are needed. Its mechanism of action is unknown: very likely it lowers
prostaglandin sintesis. Diarrhea and creeps may occur. It is contraindicated with
renal failure because of possible hypermagnesemia.
Complementary and alternative treatments of dysmenorrhea also include herbal

preparations of oriental origin, among which:
• Toki-shakuyaku-san, coming from Japan and composed by different plants, such

as angelica, peony roots, and ginger root stocks. Divided doses of 7.5 mg per day
were shown to be effective on dysmenorrhea but the results are not completely
reproducible and the evidence is poor.
• Iranian herbal preparations, using saffron, celery seeds, aniseed, with low and
very low evidences.
• Chinese herbal medicine, following traditional prescriptions, proposes a decoc-
tion of four herbs, including peony and angelica, from which capsules are derived
by watery abstraction. Fifteen capsules per day, during the first 5 days of menses
or pains, lead to a persistent improvement of symptoms after a three-cycle
administration, but evidences are few. Since long time ago in eastern countries a
variety of herbal treatments have been used to relieve dysmenorrhea with benefi-
cial effects. They mainly inhibit uterine contractions by reducing prostaglandin
secretion, suppressing cyclooxigenase-2 activity, activating superoxide dis-
mutase, stimulating somatostatin receptor with a decrease of intracellular Ca2+
and/or recovery of phospholipid metabolism [59, 60]
Further studies about safety, doses effectiveness and outcomes are required
before recommending herbal approach [8, 61].
Anecdotally, it is worth mentioning:
• Aromatherapy, proposed in Korea using lavender, sage, and rose fragrances

[62, 63].
• Rose tea, used in Taiwan to mitigate primary dysmenorrhea, improves symp-
toms, anxiety and stress, with psychological bettering just after a 1-month treat-
ment [64].
To sum up, dysmenorrhea is an important disease affecting most women of

reproductive age with important social repercussions. Even if it is difficult to quan-
tify, in adolescents it is the main cause of absenteeism from school and, if resistant
to treatments it may be an important pointer of an underlying pelvic disease [8].
Nonetheless, many adolescents don’t seek medical care because of this condition.
The subsequent algorithm summarized the most validated therapeutic approach to
primary dysmenorrhea. As endometriosis was detected in 70% teenagers undergo-
ing laparoscopy because of “resistant to treatment dysmenorrhea,” diagnostic lapa-
roscopy, if indicated, must not be delayed in adolescents, both to relieve pains and
to preserve future fertility at most [49]. Future treatments of dysmenorrhea should
5 Dysmenorrhea 93
focus on the prevention of pain more than on its management of pain to its preven-
tion [4] and clinicians should identify secondary dysmenorrhea as early as possible
to minimize its possible negative outcomes. It must also be considered that informa-
tion, education, and support, to be supplied by heath care providers both to adoles-
cents and their families, are the foundations of prevention and treatment of
dysmenorrhea [65].
5.4 Algorithm
PAINFUL MENSES:
Anterior 1–3 days long pelvic pains at the onset of menses → alleged primary
dysmenorrhea
Other clinical pictures including menstrual pains → alleged secondary
dysmenorrhea.
ALLEGED DIAGNOSIS OF PRIMARY DYSMENORRHEA
First-step approach → 6 months treatment with NSAIDs
–– If successful → treatment to be continued unchanged

–– If unsuccessful → shift to OCs
Second-step approach → 6 months treatment with OCs
–– If successful → treatment to be continued unchanged

–– If unsuccessful → alleged secondary dysmenorrhea
ALLEGED DIAGNOSIS OF SECONDARY DYSMENORRHEA
Signs and symptoms of STDs?
–– Yes → Confirm diagnosis and treat

–– No → Laparoscopy
Endometriosis?
–– Yes → Confirm diagnosis and treat

–– No → Abnormal anatomy?
Abnormal anatomy?
–– Yes →Surgical treatment

–– No →Inexplicable dysmenorrhea
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Dysfunctional Uterine Bleeding
6
Tiziano Motta, Antonio Simone Laganà,
and Salvatore Giovanni Vitale
Abbreviations
AUB Abnormal uterine bleeding

DUB Dysfunctional uterine bleeding
ESHRE European society of human reproduction and embryology
PT Prothrombin time
PTT Partial thromboplastin time
vWF:Ag Von willebrand factor
FVIII:C Factor VIII coagulant activity
FXI:Ag Factor XI
VWF:RCo Ristocetin cofactor activity
GnRH Gonadotropin-releasing hormone
FSH Follicle-stimulating hormone
LH Luteinizing hormone
TSH Thyroid-stimulating hormone
PRL Prolactin
DHEA-S Dehydroepiandrosterone sulphate
17-OHP 17-OH progesterone
OGTT Oral glucose tolerance test
PBAC Pictorial blood loss assessment chart
CBC Complete blood count
T. Motta (*)
Department of Obstetrics and Gynaecology, University of Milan—Fondazione IRCSS Cà
Granda Ospedale Maggiore Policlinico, Via Commenda, 12, 20122 Milan, Italy
A.S. Laganà • S.G. Vitale
Unit of Gynecology and Obstetrics, Department of Human Pathology in Adulthood and
Childhood “G. Barresi”, University of Messina, Via C. Valeria 1, 98125 Messina, Italy

100 T. Motta et al.
vWD Von willebrand’s disease

SLE Systematic lupus erythematosus
PCOS Polycystic ovary syndrome
SHBG Sex hormone-binding globulin
HAIR-AN Hyperandrogenism, insulin-resistance and acanthosis nigricans
syndrome
CAH Congenital adrenal hyperplasia
COC Combined oral contraceptive
NSAIDs Non-steroidal anti-inflammatory drugs
MAP Medroxyprogesterone acetate
SERM Selective estrogen receptor modulator
DDVAP Desmopressin
IUD Intrauterine device
LNG-IUD IUD containing levonorgestrel
ACOG American congress of obstetricians and gynecologists
6.1 Introduction
Abnormal Uterine Bleeding (AUB) is an atypical loss of blood from the uterine
cavity that occurs outside of the menstrual cycle. It is often a source of anxiety for
adolescents as well as their parents, who will often consult their more knowledge-
able medical doctor or gynaecologist in order to understand it better. Normal blood
loss during menstruation has been estimated to be approximately 30–35 mL/cycle
with a maximum amount of 60–80 mL/cycle [1]. The menstrual cycle commonly
lasts 7 days in a young woman (if not less) with a frequency that varies between 21
and 45 days, usually requiring the use of sanitary towels/tampons for 3–6 days [2].
In the 3 years following menarche, the cycles often present characteristics of
anovulation. However, these cycles will occur every 21–34 days in adolescents
once this period has passed. Actually, numerous clinical studies have drawn atten-
tion to the fact that over 50% of cycles in the first 2 years post-menarche are anovu-
latory, while a further 20% continue to be so after 5 years [3–5]. AUB can therefore
be considered as a form of bleeding that is irregular for quantity, duration or fre-
quency. It can also be characterised by excessive uterine bleeding that appears
regularly (menorrhagia), through massive irregular bleeding (metrorrhagia) or a
combination of both (menometrorrhagia). Sometimes, it can appear through inter-
mittent bleeding or moderate bleeding with a cyclical trend (oligomenorrhoea)
(Table 6.1).
Instead, Dysfunctional Uterine Bleeding (DUB) represents a particular type of
AUB, and is defined in the USA as an excessive, prolonged and irregular bleeding
of the endometrium (frequency <21 days; duration >7 days; daily use of sanitary
towels/tampons >1/1–2 h), that does not cause pain and does not have any organic
cause, so much so that it is frequently considered to be a symptom of anovulatory
6 Dysfunctional Uterine Bleeding 101
Table 6.1 Common terms used to describe abnormal bleeding

• Menorrhagia: regular menstrual loss per rhythm but prolonged (>7 days) or in excessive
quantities (>80 mL per cycle)
• Metrorrhagia: non-cyclic menstrual flow
• Menometrorrhagia: irregular non-cyclic, heavy and prolonged menstrual flow.
• Polymenorrhoea: menstruation with a shortened rhythm (<21 days).
• Hypermenorrhoea: menstruation that lasts >7 days.
• Oligomenorrhea: menstruation with an extended rhythm (>45 days and <6 months).
• Hypomenorrhoea: menstrual flow which is low in quantity and short in duration
• Intermenstrual Spotting: Low blood loss between two menstruations
Table 6.2 Differential diagnosis of Non-endocrine causes:

dysfunctional uterine bleeding • Coagulation disorders
• Hepatic and renal impairment
• Diabetes
• Enteric diseases
• Rheumatic diseases
• Cardiac diseases
• Neurological diseases
Endocrine causes:
• Thyroid disorders
• Hyperandrogenic alterations
• Hyperprolactinaemia
bleeding [6]. According to this definition, up to 95% of cases of adolescent AUB

would be considered DUB [7]. Conversely, the European Society of Human
Reproduction and Embryology (ESHRE) considers DUB as an excessive, intense,
prolonged and frequent bleeding of uterine origin that cannot be attributed to any
demonstrable pelvic pathology, complication during pregnancy or systemic disease.
DUB can therefore be described, in accordance with the definition provided by the
ESHRE, as either ovulatory or anovulatory, as well as presenting itself as either
acute or chronic [8]. However, the immaturity of the hypothalamic-pituitary-ovarian
axis is considered the main cause. Since DUB is a diagnosis of exclusion, other
potential causes of AUB (organic AUB) must be considered. This would include
non-endocrine (coagulation disorders, hepatic and renal impairment, diabetes, gas-
troenteric, rheumatologic, cardiac and neurological diseases) and endocrine (thy-
roid disorders, hyperandrogenic diseases, hyperprolactinaemia) causes (Table 6.2).
6.2 Adolescent Assessment
The initial assessment of an adolescent with DUB requires an accurate summary

of the patient’s medical history, both familiar (in order to exclude haemorrhagic
diatheses) and personal (previous surgery, trauma with ecchymosis, epistaxis or
gingival bleeding, previous or current pathologies, use of drugs, accurate men-
strual and sexual history), in addition to an objective medical examination (body
102 T. Motta et al.
Table 6.3 Adolescent assessment: the importance of clinical history

• Timing
• Menstrual history (age when menarche occurred; length of cycle; duration of bleeding)
• Sanitary towels/tampons (count and dimension of loss) (Pictorial blood loss assessment chart
score)
• Presence of vaginal loss
• Presence of abdominal pain
• Remote anamnesis
• Use of drugs
• Personal/family history of easy bleeding (gingival) or epistaxis and endocrine disorders
N.B. The patient should be requested to provide (in private or in the presence of relatives) informa-
tion regarding sexual history, use of contraceptives and previous sexually transmitted diseases
Table 6.4 Physical • Assessment of stage of puberty; blood pressure, height, weight,

examination body mass index
• Diagnosis of eventual clinical signs (hirsutism; petechiae or
contusions)
• Thyroid (goiter)
• Breast (galactorrhoea)
• Abdomen (presence/absence of lumps)
• Pelvis (Development of pubic hair)
In a non-sexually active adolescent, vaginal examination is rarely
necessary (abdominal ultrasound could be enough)
In a sexually active adolescent, vaginal examination is advised
mass index, stage of puberty, inspection of external genitalia with an eventual

gynaecological examination for sexually active patients, abdominal examination).
It can sometimes be useful, although not strictly necessary, to perform a pelvic
ultrasound (abdominal/transrectal or transvaginal in a sexually active patient)
(Tables 6.3 and 6.4).
Although the Italian situation differs from that of the USA, where around 62% of
17–18-years-old teenagers are sexually active [9], it is important to exclude preg-
nancy or a related complication (miscarriage or ectopic pregnancy): this can only be
done through an accurate anamnesis of the adolescent. In the USA, statistics have
drawn further attention to the fact that around 25% of adolescents will contract a
sexually transmitted infection. Since cervicitis and endometritis are both frequent
causes of heavy menstrual flow [10], if they are confirmed, it would be advisable to
investigate (or to confirm) the presence of N. Gonorrhoea and of Chlamydia
trachomatis.
A laboratory assessment should therefore be performed in accordance with the
clinical history and physical examination of the patient. The initial laboratory tests
should include pregnancy test, complete blood count (CBC), fibrinogen, Prothrombin
Time (PT) and Partial Thromboplastin Time (PTT) [11, 12]. In adolescents with a
history of heavy and prolonged bleeding, immunological dosage of von Willebrand
factor (vWF:Ag), dosage of factor VIII coagulant activity (FVIII:C), factor XI
(FXI:Ag) and ristocetin cofactor activity (VWF:RCo) could be required [11, 13]. In
suspect cases, it is good practice to request a haematological consultation. In
Table 6.5 Factors linked • Pictorial blood loss assessment chart score > 100
with a daily loss >80 mL • Heavy bleeding (>1 sanitary towel/hour)
(National Institutes of Health • Low levels of ferritin
Guidelines, 2008) • Blood clots that pass through the sanitary towel, with a
diameter of >2 cm.
adolescents who have a medical history indicative of anovulation, plasma levels of

follicle-stimulating hormone (FSH) and Thyroid-Stimulating Hormone (TSH)
should be evaluated, while in those with DUB and evident hirsutism, prolactin lev-
els (PRL), total testosterone, dehydroepiandrosterone sulphate (DHEA-S), 17-OH
progesterone (17-OHB) and androstenedione levels should be measured in associa-
tion with an oral glucose tolerance test (2 h OGTT) and the dosage of fasting insulin
and lipids [11, 13]. In order to better quantify the extent of blood loss, some authors
have suggested to use a simple and reliable semiquantitative method at home
(Pictorial Blood Loss Assessment Chart: PBAC score) [14–16], besides the above-
mentioned CBC, serum iron and ferritinemia. The daily menstrual graphic is based
on the scores that are attributed to each tampon or sanitary towel used, in relation to
the different levels of saturation observed (one use >3 towels/day in the first 3 days
of cycle, with/without blood clots, together with a menstrual loss >80 mL/day) [17]
(Table 6.5).
6.3 Blood Clotting Disorders
Adolescents who are not pregnant and do not have a sexually transmitted infection
can reveal in around 20% of cases an underlying coagulopathy [18–20], especially
if they suffer from a heavy menstrual flow. In particular, haematological causes of
DUB can be divided into two groups:
1. As a result of deficiency of coagulation factors [von Willebrand’s Disease

(vWD), deficiency of factor II, deficiency of factor V, deficiency of factor VII,
deficiency of factor X, deficiency of factor XI, fibrinogen alterations, haemo-
philia A and B]
2. As a result of alterations in platelet function (idiopathic thrombocytopenic pur-
pura, leukaemia, aplastic anaemia, Fanconi anaemia, Glanzmann’s thrombasthe-
nia, Bernard–Soulier Syndrome, renal and hepatic impairment, platelet
transfusion, cardiopulmonary bypass, drugs)
However, the most known haematological cause is vWD, whose prevalence in

the general European and American populations is estimated to be near 1% [21,
22]. Not only is menorrhagia mainly prevalent in women who show blood clotting
disorders, but these are also mainly prevalent in patients with menorrhagia. A
prevalence of 3–36% of vWD has been reported in adolescents with menorrhagia
[23]. Similarly, it has been shown that an alteration in coagulation was present in
104 T. Motta et al.
25% of adolescents with severe bleeding or haemoglobin levels <10 g/dL [24];

such levels reached 50% in cases of adolescents with menorrhagia already present
in successive cycles after the menarche [25]. Depending on the severity of symp-
toms and laboratory test results, the different variants of vWD have been classi-
fied by the International Society on Thrombosis and Haemostasis into three
different subgroups: type 1, the less severe form of factor vW deficiency (70% of
cases); type 2, in turn divided into four variants and the form due to a qualitative
defect (20–30% of cases); and type 3, the most severe and rare form of factor vW
deficiency (<5%) [26].
6.4 Renal and Hepatic Impairment
Chronic renal impairment can cause menstrual irregularities. In particular, it has

been showed that around 80% of women with chronic renal impairment suffer
from menorrhagia [27]. There are several factors that can cause the condition to
arise: (a) an increase in azotaemia often leads to irregular secondary cycles, to
central inhibition of gonadotropins and to a consequent reduction in serum oestra-
diol levels [28]; (b) elevated levels of prolactin, that occur in around 50% of
patients undergoing dialysis (due to reduced clearance), can cause DUB in adoles-
cents with renal impairment [27, 29, 30]; and (c) haematological alterations subse-
quent to renal impairment (normochromic anaemia, normocytic anaemia due to a
reduction in erythropoietin production; increased bleeding time due to a reduction
in fibrinogen, platelets and associated uraemia) can cause prolonged and severe
bleeding [23, 27, 31].
Similarly, hepatic impairment, either chronic or slowly progressive, can be linked
to blood clotting disorders (reduction in vitamin K-dependent blood clotting fac-
tors: factors II, VII, IX and X; reduction in levels of protein S, protein C, fibrinogen
and platelets) [32] or alterations in hormonal levels.
6.5 Diabetes
Menstrual irregularities, including amenorrhoea, oligomenorrhoea and menome-

trorrhagia, have been observed in adolescents with diabetes [33, 34]. In fact, hyper-
glycaemia seems to have an effect on the hypothalamic-pituitary axis, leading to a
progressive slowing-down of gonadotropin-releasing hormone (GnRH) pulsatility
and a consequent reduction in the pulsatile production of luteinizing hormone (LH)
[33–35]. DUB has been observed more frequently in adolescents with poor glycae-
mic control, especially in those with haemoglobin A1c levels above 12.8 mg/dL or
glycaemia above 240 mg/dL [33–35]. In adolescents with insulin-resistant diabetes,
DUB is the result of increased peripheral conversion of androstenedione into oes-
trone, which leads to an excessive oestrogenic response in the endometrium.
Similarly, the stimulatory effects of insulin on the ovary increase androgen produc-
tion, resulting in irregular bleeding of the endometrial mucosa.
6.6 Enteric Diseases
Alterations of the menstrual cycle have been described in patients affected by

inflammatory intestinal diseases. In fact, menstrual alterations (oligomenorrhoea,
polymenorrhoea, menorrhagia and metrorrhagia) were observed in a group of 360
women suffering from Crohn’s disease and 251 suffering from ulcerative colitis in
60% and 53% of the cases, respectively [36, 37]. The aetiology of DUB associated
with enteric pathologies is not well understood even though there is a recognised
link with the severity of the illness, stress and malabsorption.
6.7 Rheumatic Diseases
Menstrual cycle disorders have also been described in women with rheumatic dis-
eases. When compared with healthy subjects, women with juvenile chronic arthritis
have a higher incidence of metrorrhagia: in particular, menstrual disorders generally
appear after the onset of the disease [38]. Alterations in the menstrual cycle have
also been observed in around 53% of women with Systematic Lupus Erythematosus
(SLE) [39]. Increased serum levels of LH and PRL were also frequent in these
subjects.
6.8 Cardiac Diseases
In adolescents, another pathological condition that has been associated with DUB is
the cyanotic congenital heart disease [40, 41]. The mechanism through which other
alterations of the menstrual cycle are induced is currently unknown, although surgi-
cal correction time with respect to the menarche period seems to be key. In fact,
subjects under 10 years of age at the time of corrective surgery show higher regular-
ity of the menstrual cycle than subjects undergoing correction post-menarche (men-
strual cycle become regular only after 6 months following the surgery) [42]. In
subjects where the surgical repair is postponed until 6–10 years post-menarche
there is an elevated incidence of menstrual cycle alterations, with a predominance
of amenorrhoea.
6.9 Neurological Diseases
Polycystic Ovary Syndrome (PCOS) has been increasingly described in adolescents

suffering from Temporal Lobe Epilepsy (10–25%) in comparison with control sub-
jects (4–6%) [43, 44]. Furthermore, numerous studies have reported that around
40% of adolescents treated with valproic acid suffer from PCOS and 30% have
alterations in the menstrual cycle compared to adolescents treated with other anti-
convulsants [43–46]. It is believed that an increase in PCOS and DUB incidence is
a direct effect of epileptogenic lesions on the hypothalamic-pituitary axis in
106 T. Motta et al.
addition to the known effects of some antiepileptic drugs. The exact mechanism
involved is not understood, although weight gain linked to treatment with valproic
acid could play a role, since it is associated with a reduction of sex hormone-binding
globulin (SHBG) and insulin-like growth factor binding protein, which thereby
leads to an increase in androgen and PCOS [44–47].
6.10 Thyroid Disorders
It has long been known that thyroid disorders are linked with menstrual cycle
abnormalities. An increase in SHBG levels occurs during hyperthyroidism,
which leads to a similar increase in serum levels of oestradiol, testosterone and
androstenedione [48]. In subjects with DUB, hypomenorrhoea occurs in 52% of
cases, polymenorrhoea in 32.5%, oligomenorrhoea in 11% and hypermenorrhoea
in 4.5%. Conversely, in subjects with hypothyroidism a reduction in SHBG
occurs, leading to a reduced elimination of androstenedione and oestrone and an
increase of aromatase activity. The most frequently observed menstrual disorder
is menorrhagia, due probably to irregular endometrium growth secondary to an
excess of oestrogens [48]. In other cases, it can be caused by reduced levels of
factors VII, VIII, IX and XI, thereby further increasing the risk of menorrhagia
[48, 49].
6.11 Hyperandrogenic Alterations
It is widely known that androgen excess can cause DUB in adolescents.

Sometimes, the presence of menstrual alterations can be the first sign of PCOS
or other hyperandrogenic conditions. The most frequent cause of androgen
excess in adolescents is PCOS: although the exact prevalence in this population
is not known, it occurs in 3–6% of adult women [50, 51]. In addition to insulin
resistance, often related to PCOS, two other extreme conditions of PCOS can
occur (albeit more rarely): hyperthecosis of the ovary (a condition of hyperan-
drogenism in which androgen levels are higher while those of LH are lower), and
hyperandrogenism, insulin-resistance and acanthosis nigricans syndrome
(HAIR-AN) [52]. In addition to PCOS, other rare conditions of hyperandrogen-
ism in adolescents are also recognised as a cause of DUB: late-onset Congenital
Adrenal Hyperplasia (CAH), Cushing syndrome, androgen-secreting tumours,
and hyperprolactinaemia.
6.12 Hyperprolactinaemia
Elevated levels of PRL are able to inhibit GnRH secretion: intermittent secretion of
this peptide initially causes luteal phase deficiency together with polymenorrhoea,
while amenorrhoea appears when the secretion of GnRH is completely suppressed.
As mentioned above, a hyperandrogenic condition is secondary to hyperprolacti-

naemia, but it is also possible for prolactin to have a direct effect on the adrenal
gland and ovary.
6.13 Treatment
The treatment of DUB is mainly dependent on the cause (endocrine or non-

endocrine). The simple correction of the cause is often enough to improve and cor-
rect menstrual alteration: it is widely known, for example, that treatment of thyroid
disorders leads to a swift return to the normal menstrual cycle. The estimation and
consequent correction of blood loss represents the second and crucial therapeutic
objective. The most frequently proposed drugs for this specific purpose are listed in
Table 6.6.
6.14 O
estrogenic and Combined Oestro-Progestogen
Therapies
Oestrogens have long been used as initial therapy against acute DUB, especially
since 1982 when a randomised controlled trial showed that 72% of patients who
underwent two doses of oestrogen i.v. (12 h apart) stopped bleeding compared to
38% who received a placebo [53]. The single parenteral oestrogen therapy defi-
nitely has the advantage of inducing endometrial vasospasm, regenerating the
endometrial mucosa and increasing blood clotting factors. Actually, at least in
Italy, it is not possible to use it since more than a decade, due to its commercial
unavailability. The alternative is the administration of an association of combined
oral contraceptive (COC) containing at least 30 mcg of ethinylestradiol, starting
with 2–3 pills per day and subsequently reducing it to one pill per day, when bleed-
ing has reduced (after 3–4 days, on average). A review of six randomised con-
trolled trials comparing cyclic and continuous administration of a COC has
demonstrated their equivalent efficacy and compliance; however, a significantly
reduced menstrual loss was observed in the group who underwent continuous treat-
ment with COC [19, 54]. To date, there are no available data regarding the choice
of a COC over another [23].
Table 6.6 Medical therapies • Combined oral contraceptives

used to treat dysfunctional • Progestogens
uterine bleeding • Tranexamic acid and aminocaproic acid
• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Danazol and GnRH Analogues
• Medicated I.U.D.
• Desmopressin
108 T. Motta et al.
6.15 Single Progestogen Therapy
In patients with contraindications to oestrogens, progestogen is the only avail-

able option. Actually, according to Cochrane, the administration of oral proges-
togens from the 15th to 26th day of the cycle in subjects with ovulatory cycles
does not offer advantages over other medical therapies [tranexamic acid, non-
steroidal anti-inflammatory drugs (NSAIDs), Danazol, medicated intrauterine
devices (IUD)]. However, their administration can be more effective if prolonged
for at least 21 days, despite we should consider their side effects (swelling,
weight gain, fatigue, headaches/migraines, mood changes and depression) that
limit to three cycles their use [55]. According to National Institute for Health and
Care Excellence guidelines, this last method of administration is particularly
effective in women with anovulatory cycles and should represent a potential
option after non-use of other medical therapies, as a result of intolerance or their
failure [56].
As suggested by current literature, especially the American one, among the avail-
able progestogens is possible to use high doses of medroxyprogesterone acetate
(MAP 20–40 mg × 3/day): the short half-life of the drug (14 h) requires, in effect,
its administration at definitely higher dosage, as well as multiple doses spaced
closer together. This however, once again, will lead to an unavoidable increase of
side effects. For the specific pharmacological characteristics of both the molecules
(long half-life: 25–50 h with elevated biological activity in terms of secretory endo-
metrial transformation), an effective therapeutic alternative is the administration of
nomegestrol acetate (2.5–5 mg) or of norethisterone (or norethindrone) acetate
(5–10 mg). The latter also possesses a unique characteristic, since it can be con-
verted into ethinylestradiol, which is able to enhance the action of endometrial sta-
bilization [57]. In emergencies, high doses of both the molecules are recommended
and initially spaced close together. Subsequently, in case of success, doses can be
spaced further apart (Table 6.7).
Table 6.7 Emergency treatment for dysfunctional uterine bleeding (Haemoglobin <10 g/dL)
• Combined oral contraceptives containing 30–50 mcg of EE, 2–3 pills/day for 3–4 days, then
1 pill/day as part of an extended regimen
• Medroxyprogesterone acetate 10 mg (up to maximum 80 mg) every 4 h until the end of the
bleeding, then every 6 h for 4 days, then every 8 h for 3 days, every 12 h for 2–14 days and
every 24 h for the remaining period
• Nomegestrol acetate (2.5–5 mg) or norethisterone acetate (5–10 mg) every 4 h until the end
of the bleeding, then every 6 h for 4 days and subsequently every 8 h for 3 days, every 12 h
for 2–14 days and every 24 h for the remaining period
• Tranexamic acid: 10 mg/kg i.v. every 6–8 h for 2–8 days or 20–25 mg/kg as oral
administration every 8–12 h, for 5–7 days
• Aminocaproic acid: 4–5 g i.v. in 60′ every 8 h until the end of the bleeding (maximum 30 g/
day) then 50–100 mg/kg as oral administration every 3–6 h, for 5–7 days
6.16 Tranexamic Acid and Aminocaproic Acid
Due to their ability to inhibit plasminogen conversion into plasmin, these drugs
reduce fibrinolytic activity in several body areas, including the endometrium, where
they stabilize the blood clots that have formed; at high doses, a reduction of the
uterine artery flow has also been described [58, 59]. At a dosage of 15–20 mg/kg, if
started on the first day of bleeding in order to promote an immediate platelet and
fibrin aggregation, it has favourable safety profile for the management of idiopathic
metrorrhagia or for patients affected by coagulopathy [60], with a significant reduc-
tion (40–50%) of the menstrual flow [61]. Aminocaproic acid has also been success-
fully used in the reduction of excessive uterine bleeding, although it is less powerful
and causes more significant side effects than tranexamic acid, such as gastrointesti-
nal disorders (nausea and diarrhoea). These side effects are the main cause of treat-
ment cessation or dose decrease, leading to an inevitable reduction in effectiveness.
Both the drugs could be considered useful in association with other medical treat-
ments [COC, progestogen, desmopressin (DDVAP)].
6.17 Non-steroidal Anti-inflammatory Drugs
A further non-endocrine therapeutic approach may be the use of NSAIDs (naproxen

sodium, ibuprofen, mefenamic acid, etc.). Actually, their effectiveness in adolescent
DUB has only been proven in comparison with placebo (600–1200 mg/day) [63],
whereas it has not been proven with respect to tranexamic acid and medicated IUD
[19, 63]. Aspirin or NSAIDs should never be administered to adolescents with DUB
who had abnormal bleedings, until after a complete and accurate assessment (pos-
sibly also from the haematological point of view).
6.18 D
anazol, Gonadotropin-Releasing Hormone Analogues
and Clomiphene Citrate
Danazol and GnRH analogues are particularly effective in reducing heavy men-
strual flow; however, due to their well-known side effects (respectively, hyperan-
drogenism and osteoporosis) they are little used in the adolescent population and
only for limited periods, even in association with oestro-progestogen (add-back
therapy) [19, 23, 54, 62].
Clomiphene citrate, a selective estrogen receptor modulator (SERM) used as
first-line agent for anovulatory infertility in PCOS, was recently proposed as new
method to stop and prevent DUB in adolescents. After three cycles of a low-dose
therapy in 92% of the treated girls, a complete cessation of bleeding was obtained
without any hormonal or ovarian side effects [64].
110 T. Motta et al.
6.19 Medicated Intrauterine Devices
IUD containing levonorgestrel (LNG-IUD), in addition to their already known con-

traceptive properties, is currently considered as the most efficient medical treatment
for heavy menstrual flow, particularly in women with blood clotting alterations [65,
66]. Since 2007, the American Congress of Obstetricians and Gynecologists
(ACOG) [67, 68] has concluded that the available data in literature confirm the
safety of IUD, even in adolescents; actually, the experience in the specific treatment
of DUB is still scarce. One randomized trial developed in Finland on 200 young
patients (18–25 years) with regular menstrual cycles and undergoing treatment with
LGN-IUD or COCs found a significant reduction of bleeding in the LGN-IUD
group (49.3 vs. 22%; p < 0.001), although by subjective evaluation [69]; another
study developed in New Zealand on 133 adolescents (11–19 years) found 85% of
maintenance rate of device and only 8% of expulsion, comparably with adult popu-
lation [70], and reduction of bleeding in five adolescents affected by blood clotting
disorders (100% of cases), without any relevant side effect apart from well-tolerated,
moderate spotting [62]. Menstrual cycle control effectiveness was also described
after the use of LNG-IUD in an adolescent suffering from vWD disease refractory
to previous treatments with high dose COCs, GnRH analogue, etonogestrel subder-
mal contraceptive implant and aminocaproic acid [71].
6.20 Desmopressin
Desmopressin is a synthetic analogue of the antidiuretic hormone vasopressin. The

molecule is able to increase platelet adhesiveness and plasmatic concentrations of
circulating vWF:Ag and FVIII. Its administration is therefore suggested for the pre-
vention and treatment of bleeding in patients affected by vWD and haemophilia. It
is administered at home via nasal spray (150–300 μg) or in a hospital environment
s.c. or i.v. at a dose of 0.3 μg/kg, however not for more than two consecutive admin-
istrations in a 12 h interval. Its administration is also limited to the first 2–3 days of
heavy flow, especially for its secondary effects of tachyphylaxis on endothelial vWF
deposits, tachycardia, headaches, nausea and fluid retention (risk of hyponatremia).
Literature data suggest a greater therapeutic efficacy when administered (at lower
doses and therefore with a lower risk of side effects) in association with tranexamic
acid, rather than alone [72]. However, its effectiveness is considered to be similar
both after single administration and together with COC [62, 73].
Only in case of real failure of the above-mentioned medical treatments, it is pos-
sible to perform dilation and curettage of the uterine cavity. Considering also that
the risk of endometrial cancer during adolescence is approximately 0.1/100,000
women, this procedure is suggested by the ACOG only for obese adolescents with
persistently anovulatory cycles for a period longer than 2 years [74]. Some authors
suggest as an alternative to use intrauterine application of a Foley catheter (16–18
French) filled with at least 30 cc of water (Balloon) and maintained in situ for a
period no longer than 24 h [75].
Some indications for the management of the differing degrees of DUB have been
summarised below for further utility (Tables 6.7, 6.8 and 6.9).
Table 6.8 Treatment of adolescents with minimal or moderate bleeding

Entity of bleeding Hb (g/dL) Management/treatment
Minimal (flows longer than normal or >12 • Reassurance.
shorter cycles for ≥2 months) • Menstrual calendar.
• Iron supplementation.
• Periodic reassessment.
Moderate (moderately prolonged 10–12 • Reassurance.
flows or short cycles with frequent • Menstrual calendar.
flows—every 1–3 weeks) • Exclude sexually transmitted diseases
and blood clotting alterations.
• Iron supplementation.
• Cyclic progesterone therapy or
combined oral contraceptive at low
doses.
• Reassessment <6 months
Table 6.9 Treatment of adolescents with severe bleeding

Entity of bleeding Hb (g/dL) Management/treatment
Severe (without bleeding <10 • Exclude coagulopathies.
present) • Iron supplementation.
• Hormone therapy (combined oral contraceptive/
progestogen)
• Tranexamic acid.
• Reassessment <6 months.
Severe (acute <10 • Transfusion.
haemorrhage) • Integrate liquids.
• Hormonal haemostasis (combined oral
contraceptive 2–3/g for 3–4 days).
• Tranexamic acid.
• Uterine dilation and curettage if hormonal
haemostasis fails (rare).
• Follow-up with combined oral contraceptive/
progestogen.
Hypovolemic shock <5–6 • Stabilisation.
• Transfusion.
• Exclude coagulopathies.
• Administration of combined oral contraceptive at
higher doses until haemorrhage is blocked
• Tranexamic acid
• Dilation and curettage, or tamponing with balloon
in extreme cases
112 T. Motta et al.
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Menstrual Disorders in Post-menarcheal
Girls 7
Francesca Pampaloni and Pina Mertino
Abbreviations
AAP Atypical AntiPsychotics

ACTH Adrenocorticotropic hormone
BCM Body cellular mass
BIA Bioelectrical impedance assessment
BMD Bone mineral density
BMI Body mass index
CCK CholeCystoKinin
CNS Central nervous system
CRH Corticotropin-releasing hormone
CVD Cardiovascular disease
DM Diabetes mellitus
DXA Dual energy X-ray absorptiometry
D2 Dopamine receptors 2
E2 Estradiol
FHA Functional hypothalamic amenorrhea
FMR1 Fragile X mental retardation protein
FSH Follicle stimulating hormone
fT3 Free thyroxine 3
fT4 Free thyroxine 4
GALT Galactose-1-phosphate-uridyl-transferase
GLP-1 Glucagon like peptide-1
HRT Hormone replacement therapy
F. Pampaloni, M.D. (*) • P. Mertino, M.D.

Pediatric and Adolescent Gynecology Unit, Careggi Hospital, Florence, Italy

118 F. Pampaloni and P. Mertino
IBD Inflammatory bowel disease

IGF-1 Insulinlike growth factors-1
LH Luteinizing hormone
MRI Magnetic resonance imaging
PCOS Polycystic ovary syndrome
POI Premature ovarian insufficiency
PRL Prolactin
SLE Systemic lupus erythematosus
TIDA Tubero infundibular dopaminergic neurons
TRH Thyrotropin-releasing hormone
TSH Thyrotropin stimulating hormone
T2DM Type 2 diabetes mellitus
7.1 Pathophysiology of Post-menarche Menstrual Function
Girls, during adolescence, go through the maturation of a complex endocrinological

system, which involves the hypothalamus, the pituitary gland, the ovaries and their
interactions. All the above should lead to a healthy reproductive function, but it
doesn’t occur immediately, so, in postpubertal girls we can find frequent menstrual
disorders like polymenorrhea and oligomenorrhea (Tables 7.1 and 7.2) [1–4].
Menstrual irregularity is virtually always the result of anovulatory cycles. However,
the opposite is not always true monthly, menstrual regularity does not necessarily
indicate underlying regular ovulatory cyclicity. Within 1 year after menarche, men-
strual regularity approximates adult standards in most girls, although there is consid-
erable interindividual variation in the time it takes for menstrual cyclicity to mature [1,
4]. Average menstrual cycle length is 21–45 days in 75% of girls 1 year post-men-
arche, and further 5% falls within these bounds for each of the following 3 years [5,
6]. During the first 2 post-menarcheal years, about half of menstrual cycles are anovu-
latory, but the duration half of these anovulatory cycles is 21–45 days [2, 3, 6].
Table 7.1 Pathogenesis Functional immaturity

of menstrual disorders in Central (hypothalamic) Physical/emotional stress
girls Low energetic intake
Chronic diseases
CNS organic pathology
Prolactin excess
Ovary PCOS
Hormone secreting ovarian cysts
POI
Endocrinopathies Hypo/hyperthyroidism
Adrenogenital syndrome
Cushing syndrome
Internal genitalia Uterine synechiae
Acquired vaginal stenosis
Pregnancy
7 Menstrual Disorders in Post-menarcheal Girls 119
Table 7.2 Definitions
Secondary amenorrhea Absence of bleeding in girls >180 days, Europe
Absence of bleeding in girls >90 days, USA
Oligomenorrhea Intervals between cycles >45 days (gynecological age > 2 years)
Less than 8 cycles per year
Polymenorrhea Intervals between cycles <21 days
Table 7.3 Normal period

What is a normal Menarche before 15
period? Last 1 week or less
21–45 days from the first day of one period to the first day of the next
period
During bleeding, the girl fills less than one pad per hour
Reproduced with permission from [8]
Thus, normal menstrual frequency is much greater than ovulatory frequency.

Within the first 5 gynecological years, 95% of menstrual cycles lasts 21–40 days,
and about 75% of cycles are ovulatory; over the next several years the mature
menstrual pattern is established with approximately an 80% ovulatory rate.
During the following years the menstrual pattern is mature, and consequently
ovulatory, in about 80% of cases [2, 3, 6]. As earlier age of menarche is associ-
ated with earlier ovulatory maturation, the opposite applies and late maturation
[7]. Normally adolescent anovulation causes only minor menstrual cycle irregu-
larity (Table 7.3).
7.2 Functional Immaturity
Normal, pubertal maturation, menstrual function requires a series of neuroendo-

crine steps involving numerous districts of the body that can provide a physiological
latency. Ovarian follicular structures, i.e., granulosa cells and theca cells, may expe-
rience a period of mild dysfunction due to the immaturity of their cross-talk mecha-
nisms and, probably, to the elevated stimulus on the ovary by physiologically
increased insulin concentrations. In these cases of functional immaturity, androgen
production by thecal cells (mainly androstenedione) is increased but their aromati-
zation in estradiol is reduced, leading to a delay in follicular maturation with oligo-
menorrhea as clinical manifestation.
7.3 Functional Hypothalamic Amenorrhea (FHA)
FHA includes all clinical conditions characterized by stress, low energetic intake,
intense physical activity, and chronic disease affecting metabolic homeostasis.
7.3.1 Mean Pathogenic Mechanisms
In a dangerous, acute situation the production of norepinephrine (also responsible for

the feeling of fear) from locus coeruleus starts. In the same time, norepinephrine
increases production of CRH with activation of hypothalamus–pituitary–adrenal axis
and of sympathetic autonomous nervous system. The answer to stressing stimuli is
mediated by β-endorphin, even if modulated by genetic variables. All physiological
functions not fundamental for survival are restricted, as the ovarian function. The
anatomic and functional proximity between GnRH-gonadotropin axis and CRH-
ACTH axis allows rapid short inhibitory mechanisms on reproductive function in
response to stress hormone hyperproduction. In a chronic stress state, the answer to
chronic stimuli is modulated by feedback of rearrangement, acting through the same
pathway of increased limbic–hypothalamic–pituitary–adrenal axis activity [9] and
reduced central gonadotropin-releasing hormone (GnRH) drive [10–12].
Of note, stress and its resulting hormonal changes could trigger either undernu-
trition or overnutrition, depending on fuel availability, attitudes about food, and
dietary behaviors such as bingeing, purging, overeating, or restricting. The answer
to hormonal stress depends on age and weight, for this reason in adolescence it is
stronger than in adults.
The energetic homeostasis is another crucial point to allow physiological reproduc-
tive function. Vagal nerve is the principal nervous input to central nervous system
(CNS); this nerve is connected to gastric distension and cholecystokinin (CCK) and
glucose production. Peripheral endocrine signals are various: leptin and adiponectin
are signals produced by adipose tissue acting as feedback on hypothalamic nuclei regu-
lating feeding and reproductive control. On the contrary, ghrelin, produced by cells of
stomach fundus, is a short-term signal of energetic request. Both leptin and ghrelin play
their role, respectively inhibitory and stimulating on appetite center, through arcuate
nuclei, probably through pro-opiomelanocortin and the peptides derived from its cleav-
age. The feedbacks from other peripheral hormones produced by gastrointestinal tract
are integrated at hypothalamic level: Peptide YY, GLP-1, Insulin, and Pancreatic poly-
peptide. These peripheral endocrine messages mix their information to hypothalamus
with central afferences (as endocannabinoids and oxytocin).
The inhibitory effect of energetic deficit on hypothalamic function is a key point
in menstrual dysfunctions of adolescent athletes, due to strenuous exercise some-
times associated to inadequate energy intake. This can be expressed by inappropri-
ate luteal phase, anovulatory cycles, oligomenorrhea, or secondary amenorrhea. It
is important to keep in mind that the same endocrine system that binds energetic
restriction and menstrual alteration produces effects on bone turnover, increasing
reabsorption and reducing neoformation in the adolescent age, causing a problem in
reaching or maintaining peak bone mass.
Amenorrhea, low bone density, and eating disorders, the so-called “Athletic
Triade,” expose these girls to high risk of stress fractures. Stress fractures are nor-
mally not due a single traumatic event, but to multiple bone stresses. The bones
most frequently interested are tibia, metatarsi, and navicular, due to their particular
exposure to micro traumatic events.
7.3.2 Diagnosis
Functional hypothalamic amenorrhea is a diagnosis established after exclusion of

other conditions having similar manifestation. The diagnostic workup should be
based on the history of menstrual disorders. In the majority of cases normal menses
with ovulatory cycles are followed by gradual loss of ovulation, then the menses
become rare till they completely disappear. A lack of menarche can also be the main
manifestation of FHA in early pubertal girls (Chap. 2). A careful clinical history is
essential for identifying these patients; familiar osteoporosis, low birth weight,
bowel malabsorption, previous fractures, late menarche, and low sun exposition are
also important factors for bone mineral density deficiency; the number of hours of
physical activity per day or week, eating diary, and menstrual diaries are also useful.
Family conflicts, problems with the peers, school difficulties, and stressful events
should also be investigated. The measure of height and weight and body mass index
(BMI) is fundamental. DXA (Dual energy X-ray Absorption) and BIA (Bioelectrical
Impedance Assessment) are useful tools to assess body composition. The imped-
ance assessment is based on low frequency electric energy modifications passing
through the body. The attenuation (resistance) is mainly due to the presence of
water, which is mainly related to muscle mass. This exam primarily evaluates hydra-
tion and nutritional state. Generally, a good hydration should be around 60% and
lean mass 78–80%. The measure of fat mass is indirect and for this reason is not
totally reliable. Athletic girls often present reduced levels of intracellular water due
to thermoregulation induced by physical effort. The body cellular mass (BCM)
expresses the metabolically active part of the body: a cutoff level of 7 is considered
expression of undernutrition. The DXA total body is a more precise mean of study-
ing body composition, even if it is expensive and minimally radiant. It consents the
evaluation of Bone Mineral Density (BMD) using references for age. Ultrasound
pelvic is a useful complementary examination because endometrial thickness is an
indirect measure of estradiol levels. Ovary echo-structures can be extremely vari-
ous: multi-follicular or micro-follicular with low vascularization to color Doppler
(Table 7.4).
We can use progesterone challenge test to check the endometrial estrogenization
[13]; performing the test blood sampling for hormonal profile can take place during
bleeding. In the past medroxyprogesterone acetate 10 mg for 10 days has been
extensively used: menstrual bleeding could be expected with an endometrial thick-
ness >6 mm. Nowadays micronized progesterone 100 mg/day twice/day for 10 days
is preferred, but it doesn’t exist yet a definition of endometrial thickness related to
the bleeding answer.
Table 7.4 Endocrine clues Plasmatic cortisol towards elevated value

of FHA LH towards low level with FSH and PRL within normal range
IGF-1 towards low level
fT3 towards low level, fT4 and TSH within normal range
Insulin towards low level with normal glucose levels
FSH and PRL in the normal range
7.3.3 Management
Treatment of menstrual disorders, and secondary amenorrhea resulting from hypo-

thalamic disorders should be aimed at the elimination of the primary cause, i.e., a
decrease in psycho-emotional strain, avoidance of chronic stressors, reduction of
physical exercise level, or optimization of BMI in patients who lose weight [14].
A cognitive-behavioral therapy can be proposed to help coping with stress
response or modifying habits related to diet and physical exercise, working on body
image difficulties or problem-solving skills. A reduction of stress response and the
restoration of metabolic equilibrium is the main street to resume normal menses and
ovulation. Usually, menstrual function resumes spontaneously as a result of lifestyle
modification or of environmental changes (e.g., changing school).
If menses do not resume after a period of 6 months or primary causative treat-
ment is not possible, e.g., in competitive athletes or ballet dancers, neutralization of
hypoestrogenism consequences especially unfavorable effects on bone metabolism
becomes the main issue. Hormonal preparations should be introduced into thera-
peutic protocol on an individualized basis; the patient’s expectations with regard to
treatment outcomes should also be considered. In situations with long-lasting low
energy intake, the bone sparing effect of estroprogestins is probably ineffective.
7.4 Chronic Diseases
Systemic diseases affecting metabolic homeostasis can induce menstrual dysfunc-

tion and bone impairment.
Congenital bile atresia: Rare, inflammatory damage to intra-extra hepatic bile
ducts with bile tree sclerosis and narrowing up to obliteration.
Celiac disease: The disease is an immune-mediated inflammatory enteropathy
triggered by gluten exposure in genetically susceptible individuals. It has a high
prevalence approaching 1% but it is very poorly diagnosed. The enzyme transgluta-
minase, through deamidation, modifies gluten, so the protein is presented like an
antigen and triggers a systemic inflammatory reaction. Several studies have shown
that celiac disease, mostly if not recognized, can impair women’ reproductive life
eliciting delayed puberty, infertility, amenorrhea, and early menopause [15].
Therapy is a gluten-free diet.
Systemic lupus erythematosus (SLE) is an autoimmune disorder; during its active
phases, it may affect the hypothalamic–pituitary functioning and reproductive
health status. Additionally, cyclophosphamide treatment can affect gonadal func-
tion [16].
Inflammatory bowel disease (IBD) is an autoimmune disease related to individ-
ual genetic susceptibility, modifications of gut microbiota, and trigger events that
modify the physiological immune barrier inducing an inflammatory chronic condi-
tion. Menstrual disorders occur commonly in women with Crohn’s diseases, linked
both to malabsorption and to the elevated inflammatory reaction, present even in the
years preceding the diagnosis. In these patients, we prefer the use of progesterone
with natural estrogen rather than hormonal contraceptive due to theirs higher level
of thromboembolic risk, related to pathology. The treatment of the underlying con-
dition is the main therapeutic aid.
Chronic kidney disease: Girls with kidney dysfunction often experience men-
strual disorders especially patients in dialysis. Malnutrition and modification in
body composition are probably the main pathogenetic factors. As a treatment it is
possible to use progesterone or progestins.
7.5 Hyperprolactinemia
An increase in circulating prolactin (PRL) levels may reveal itself with menstrual
disturbances. 5.5% of menstrual dysfunction in adolescents are due to hyperprolac-
tinemia. Hyperprolactinemia is not a unique disease per se; rather, it has multiple
etiologies [17–19] (Table 7.5).
PRL size is heterogeneous in terms of circulating molecular forms. The predomi-
nant form in healthy subjects and in patients with prolactinomas is monomeric
PRL. Dimeric or big PRL (45–60 kDa), and big-big PRL or macroprolactin (150–
170 kDa) correspond to less than 20% of the total PRL Though still controversial,
studies indicate that macroprolactin has both low bioactivity and bioavailability
[20–23], thus explaining why most patients with increases in macroprolactinemia
lack typical symptoms related to hyperprolactinemia [22–24].
Considering prevalence, prolactinoma is the most common cause of chronic
hyperprolactinemia, followed by drugs stimulating PRL production, pseudoprolac-
tinoma, pregnancy, and primary hypothyroidism.
Prolactin secreting pituitary adenomas or prolactinomas represent the most com-
mon type of pituitary adenoma (about 40%) being the main cause of pathological
hyperprolactinemia [17–19]. Pituitary adenomas secreting PRL can be distin-
guished in micro if they are <10 mm and macro if they are bigger than 10 mm.
The term pseudoprolactinoma is comprehensive of all compressive situations
that disrupt or reduce inhibitory connections (Tubero Infundibular Dopaminergic
neurons or TIDA) between hypothalamus and pituitary. They may be not function-
ing adenomas, tumors as craniopharyngiomas, traumatic lesions, infective, infiltra-
tive or vascular pathologies that reduce the hematic flow or directly damage the
neurovascular bundle.
Table 7.5 Causes of hyperprolactinemia

Pituitary macro/microadenoma PRL secretion or multiple endocrine secretion
Pseudoprolactinomas Tumors, infiltrative lesions, vasculitis, traumatic
outcomes
Hypophysitis lymphocytic autoimmune Consequence of inflammatory process
Empty sella syndrome
Primary hypothyroidism
Idiopathic
Drugs
Autoimmune lymphocytic hypophysitis is generally the consequence of an

inflammatory process affecting the whole gland or only the infundibular-posterior
region, with autoimmune partial parenchyma destruction and consequent hypofunc-
tion. It can alter menstrual cycle both through with hyperprolactinemia and low
level of FSH and LH.
A primary empty sella syndrome is characterized by the increase of cerebrospi-
nal fluid through a hole in the sella diaphragm, with compression of pituitary paren-
chyma. It is often asymptomatic, but it can sometimes appear with hyperprolactinemia
and intracranial hypertension. Secondary empty sella is mainly related to
hypophysitis.
In case of untreated primary hypothyroidism, we can register an increase of pro-
lactin due to drag effect of TRH.
We define an idiopathic hyperprolactinemia if specific causes are not evident and
the imaging is negative; in about 30% of cases, the levels of the hormone will rees-
tablish spontaneously.
A high level of prolactin due to drugs is very common in the adolescent girls.
Drugs act through different mechanisms: increased transcription of PRL gene
(estrogens), antagonism of dopamine receptor (risperidone, haloperidol, metoclo-
pramide, domperidone, sulpiride, etc.), dopamine depletion (reserpine, methyl-
dopa), inhibition of hypothalamic dopamine production (verapamil, heroin,
morphine, enkephalin analogs, etc.), inhibition of dopamine reuptake (tricyclic
antidepressants, cocaine, amphetamine, monoamine oxidase inhibitors), inhibition
of serotonin reuptake (opiates, fenfluramine, fluoxetine, sibutramine), etc. [19,
26–31].
Among antipsychotics, the most frequently involved are haloperidol, pheno-
thiazine, and risperidone, while tricyclic drugs are the main observed among the
antidepressants. Other studies [26] found the following rates of hyperprolac-
tinemia associated with each therapeutic drug class: 31% neuroleptics, 28%
neuroleptic-like drugs, 26% antidepressants, 5% H2-receptor antagonists, and
10% other drugs. The newer atypical antipsychotics (AAP) are characterized by
increased antipsychotic efficacy, and fewer neurological and endocrine related
side effects as compared to classical antipsychotic drugs. With the exception of
risperidone, amilsulpride, and molindone that are often associated with high PRL
levels [32], most of AAP elicit poor hyperprolactinemic response or no hyperp-
rolactinemia at all [28]. Furthermore, addition of drugs like quetiapine and
aripiprazole has been shown to reverse the hyperprolactinemia induced by other
AAPs [29].
The evaluation of drug-induced hyperprolactinemia can be challenging; it is
noteworthy to consider the concomitance of a pathologic cause. In an ideal situ-
ation, if the severity of the disease consents and is corroborated by a psychia-
trist, it is recommended to perform repeated PRL measurements after
discontinuing the medication for at least 3–4 days. When drug withdrawal is
unsafe, an MRI should be performed to rule out a sella mass. If drug-induced
hyperprolactinemia is confirmed, the switch to an alternative medication is the
safer option [25, 30].
7.5.1 Diagnosis
The diagnosis of hyperprolactinemia is based on repeated findings (two at least) of

an increase of PRL serum concentration (above 25 ng/ml or 600 UI/l in women).
Blood samples should be collected in the morning in the patient in fasting state, who
should be in a comfortable setting after a good night’s sleep at least 2–3 h after wak-
ing up (samples drawn earlier may show sleep-induced peak levels). The TSH and
IGF-1 dosage is a useful tool to confirm the diagnosis. Magnetic resonance imaging
(MRI) with gadolinium as a contrast mean virtually visualizes all macroprolactino-
mas (diameter ≥10 mm) and pseudoprolactinomas, as well as most microprolacti-
nomas (diameter <10 mm) [32–34]. In case of macroprolactinomas is worth a check
of visual field.
7.5.2 Therapy
D2 receptor agonists induce the inhibition of stored PRL and the reduction of its
synthesis and secretion through suppression of gene. A daily dopamine agonist
administration can produce side effects such as nausea and vomiting; for these rea-
sons it is worth starting with the lowest dose, monitoring the hormone plasma lev-
els. Bromocriptine is less effective in adolescent microadenomas. Cabergoline is the
drug of choice because it is characterized by a long half-life, low clearance and
enterohepatic circulation.
The treatments with dopaminoagonist could, even if rarely, cause cardiac valves’
lesions, so an echocardiogram in prolonged treatments is recommended. In patients
with hyperprolactinemia, we can use also oral estroprogestin. In case of no symp-
toms, with negative imaging, the necessity of therapy is under debate.
7.6 Secondary Menstrual Disorders
In case of Congenital Adrenal Hyperplasia, menstrual cycles are irregular for higher
levels of progesterone in follicular phase.
Cushing Syndrome is not so common in adolescent period and it is characterized
by high level of cortisol. An increase in free urinary cortisol is required for the
diagnosis.
7.6.1 Dysfunctional Thyroid
Hashimoto’s thyroiditis (HT), the most common autoimmune thyroid disease at any
age, is often associated with other autoimmune diseases.
Girls with hypothyroidism suffer from menstrual irregularity three times more
than general population. In hypothyroid patients, TRH increases stimulation of both
TSH and PRL and a deficit in LH production with inadequate luteal phase has also
been observed; reduction of SHBG, estradiol and testosterone circulating levels

reduce endometrial growth.
In case of hyperthyroidism, we can find higher level of estrogen due to increase
of SHBG and heavy menstrual bleeding.
7.7 Premature Ovarian Insufficiency (POI)
Numerous studies are available on the pathophysiology of premature ovarian insuf-

ficiency (POI). Spontaneous POI involves the precocious cessation of normal ovar-
ian function, causing infertility, menopausal symptoms, and general health concerns.
It affects approximately 0.1% of women under 30 years [35, 36].
There are multiple etiologies for primary POI, including genetic, autoimmune,
and idiopathic presentations, but also iatrogenic related to chemotherapy or radia-
tion, or pelvic surgery.
In adolescent girls, gonadal dysgenesis revealing after menarche is a frequent
cause of gonadal defect (see Chap. 4). The most common genetic cause of POI is
Turner syndrome, affecting about 1: 2500 girls [37] characterized by aneuploidy of
X chromosome. But spontaneous 46, XX POI with ovarian insufficiency in girls
with normal karyotype is frequent and related to various gene mutations related to
X chromosomes or to autosomes.
A premutation in the Fragile X Mental Retardation 1 (FMR1) gene is responsible
for an estimated 2–5% of cases of isolated sPOI and 14% of familial sPOI cases [37,
38]. The FMR1 gene contains a polymorphic trinucleotide (CGG): more than 200
CGG repeats cause fragile X syndrome, the most common heritable form of mental
retardation. The FMR1 gene premutation, which may expand to the full mutation
across generations, contains 55–199 CGG repeats, and entails about 24% risk of
developing POI in carriers [37].
Approximately 4% of sPOI cases are due to lymphocytic autoimmune oophoritis
caused by autoimmunity against steroidogenic cells, a process that may affect func-
tion of both the ovary and the adrenal glands [39, 40].
Classic galactosemia (ORPHA-79239) is caused by deficient activity of
galactose-1-phosphate uridyl transferase (GALT), as a result of mutations in the
GALT gene located on chromosome 9p13. GALT is the second of the three enzymes
in the Leloir pathway, the main pathway of galactose metabolism. The incidence of
classic galactosemia varies between 1:16,000 [41] and 1:60,000 [42] in Western
countries. Galactose is needed for energy metabolism and glycosylation of complex
molecules. It may be derived from exogenous (dietary) sources, most importantly
lactose from dairy products, or endogenous production. Deficiency of the GALT
enzyme leads to accumulation of galactose and its metabolites and results in sec-
ondary glycosylation abnormalities. Patients usually present in the first weeks of
life with signs of liver and renal disease, cataracts, and an Escherichia coli sepsis.
Diagnostic tests include elevated galactose and galactitol in body fluids, elevated
Gal-1-P in erythrocytes, severely diminished enzyme activity in erythrocytes, and
mutations in the GALT gene. A galactose-restricted diet quickly resolves the early
signs, but cannot prevent the development of later-onset complications, such as cog-
nitive impairment, neurological sequelae, bone health abnormalities, and, in female
patients, POI with subsequent infertility. Although POI in classic galactosemia rep-
resents a major concern for these patients and/or their parents [43], there are no
published recommendations concerning fertility preservation in this group [44].
Symptoms of POI differ between affected women, varying from subfertility, to
early development of irregular menstrual cycles and infertility, to primary amenor-
rhea and absence of spontaneous puberty [45]. The cause of POI in classic galacto-
semia is not yet understood. Several mechanisms have been postulated, including
direct toxicity of metabolites (i.e., galactose-1-phosphate), altered gene expression,
or aberrant function of hormones and or receptors due to glycosylation abnormali-
ties [46–49]. It is also possible that not one, but several mechanisms act in unison to
cause POI in classic galactosemia.
In general, POI can be caused by either the formation of a smaller primordial
follicle pool or more rapid loss of primordial follicles [45] and there is evidence for
both mechanisms in classic galactosemia. In classic galactosemia, there is some
evidence that the follicle pool at birth is as large as in girls without this disease [44].
An immune-mediated premature ovarian insufficiency could be associated in some
case of thyroidits immune-mediated, Addison and dyabets and many others immune-
mediated disease. Many targets have been identified in the ovary: steroid secretion,
gonadotropin, and oocyte. Many of the health complications associated with POI are
directly related to ovarian hormone deficiency, primarily estrogen deficiency. They
include menopausal symptoms (hot flashes, night sweats, insomnia, dyspareunia,
decreased sexual desire, and vaginal dryness), decreased bone mineral density (BMD)
and increased risk of fracture, infertility, increased risk of mood disorders, namely,
depression and anxiety, cognitive decline, sexual dysfunction, increased rates of auto-
immune disease, increased risk of cardiovascular disease, increased risk of type 2
diabetes mellitus (T2DM) or pre-DM, and dry eye syndrome [39].
7.7.1 Diagnosis
The most commonly applied definition of POI is 4 months of amenorrhea, with

serum levels of FSH greater than 40 IU/L on two occasions. Dosage of FSH >30
UI/l twice, even if an FSH level >15 UI/l in adolescent, is already significant for an
ovarian damage. The level of anti-mullerian hormone (AMH) produced by granu-
losa cells follicle can give us an estimate of ovarian reserve.
Pelvic ultrasound is useful to measure ovarian volume and to perform the antral
follicle count. Ovarian volume in these patients is reduced, and cutoff is <6 cm3;
antral follicles are those with diameter between 2 and 10 mm; in a normal condition
they should be between 3 and 8 per ovary. The minimum amount in both ovaries is
10 antral follicles.
In case of autoimmune etiology, we must check autoantibodies. Generally, we
check autoantibodies directed to ovarian cell, against thyroglobulin, TRH, adrenal
cells, and gastric mucosa.
In these patients it is also important to measure basal bone mineral density (espe-
cially in patients treated with chemotherapy during infancy), and to propose specific
counseling for bone loss prevention: physical activity, diet, and vitamin D supple-
mentation if required.
Genetic counselling, extended to other familiar, is particularly useful in case of
FMR1 premutation; but it could be of interest also in X aneuploidies or other known
mutations.
In subjects with previous antineoplastic treatment a thorough clinical and labo-
ratoristic evaluation, considering also thromboembolic risk, is mandatory before
choosing the hormonal therapy. A cardiological evaluation after chemotherapy in
case of use of cardiotoxic drugs is also advised. In subjects recovered from Hodgkin
disease extended to mediastinal area, we recommend strict mammary control for the
well-known higher risk of breast cancer after radiotherapy.
If it is possible for a very precocious diagnosis we can suggest the patient an
oocyte cryopreservation.
In case of POI, the communication of the diagnosis with the patient is very heavy,
because they often do not accept their condition and can remove the information we give
them. In our experience the possibility of a psychological counselling is precious.
7.7.2 Therapy
It is widely accepted that the mainstay of treatment of POI is hormone replacement

therapy (HRT). The choice of HRT should closely mimic normal ovarian steroid
hormone production and provide sufficient levels of E2 to reduce menopausal symp-
toms, maintain bone density, minimize psychologic impacts of estrogen deficiency,
and protect against early progression of CVD and dementia [37]. In these patients it
is very important for a very precocious start of hormonal therapy for ensuring a cor-
rect genital tropism and minimizing endothelial dysfunction due to hypoestrogen-
ism. For these patients, especially those with presumptive autoimmune disorder, the
possibility of pregnancy is very low but it exists and we have to inform them about it.
We usually prescribe oral or transdermal estradiol; the transdermal route is more
advisable if a minimal venous risk is suspected. Risk of venous thromboembolism
is increased by oral estrogen compared with transdermal estrogen use [35, 50–53].
An adequate dosage for estradiol in this age range is about 75–100 mcg transder-
mal and 1.5–2 mg per os daily. The individual variability of absorption, especially
for oral route, is very wide. So we suggest to check the clinical answer through
ultrasound examination evaluating uterus dimension and endometrial thickness and,
in some cases, the dosage of 17 β estradiol in precocious follicular phase.
The progestin component of HRT for women with POI should be cyclical and
will protect the endometrium by inducing regular withdrawal bleeds. Natural pro-
gesterone or dydrogesterone is preferable because of the low metabolic impact.
HRT should be continued until the age of natural menopause, at which time the dose
may be tapered to postmenopausal levels or stopped, depending on a woman’s spe-
cific risks and needs.
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Eating Disorders in Adolescence
8
Vincenzina Bruni and Metella Dei
Abbreviations
ADH Anti diuretic hormone

ALMI Appendicular Lean Mass Index
AN Anorexia nervosa
ARFID Avoidant/restrictive food intake disorder
ARP Agouti-related protein
BCMI Body Cell Mass Index
BIA Body impedance assessment
BMC Bone mineral content
BMD (areal) Bone mineral density
BMI Body Mass Index
BN Bulimia nervosa
CCK Cholecystokinin
DSM Diagnostic and statistical manual of mental disorders
DXA Dual X-ray absorptiometry
ED Eating disorders
FFM Fat free mass
FSH Follicle-stimulating hormone
FT3 Free 3-jodo-thyronin
V. Bruni
University of Florence, Florence, Italy
M. Dei, M.D. (*)
Italian Society of Pediatric Adolescent Gynecology E.B,
Florence, Italy

132 V. Bruni and M. Dei
Gh Growth hormone
GI Gastrointestinal
GLP-1 Glucagon-like peptide 1
IGF-1 Insulin-like growth factor
IGFBP Insulin-like growth factor binding protein
LH Luteotropic hormone
NPY Neuro peptide Y
PP Pancreatic polypeptide
REE Resting energy expenditure
SGOT Serum glutamic oxaloacetic transaminase
SHBG Sex hormone binding protein
SRIs Serotonin reuptake inhibitors
TBW Total body water
8.1 Definition and Pathogenesis
There is increasing evidence that distress about shape and weight, behaviours of
food restriction, and loss of control over eating are more common than previously
thought in very young people [1]. The epidemiology and the real impact of these ED
behaviours in pre-adolescents and adolescents is probably not clear because it is
partially an underground phenomenon. Moreover, different behaviours such as food
avoidance, strenuous exercising, and bingeing episodes are often mixed, so our cur-
rent diagnostic categories could not be sensitive enough for this age group. For a
general diagnostic framework, we refer to the DSM5 criteria [2] summarized in
Table 8.1.
In adolescents strictly selective food intake, recurrent functional gastrointestinal
symptoms impairing normal feeding and physical activity measured on estimated
caloric intake are very common behaviours. Therefore, they often move in a “grey
area” of eating disorders, sometimes presented as healthy habits, more difficult to
discover.
From the point of view of the gynaecologists, the identification of an ED is piv-
otal in clinical situations where the reduced energy availability disrupts
hypothalamus-pituitary-ovarian axis function inducing pubertal delay or amenor-
rhoea. It is important to stress that all eating disorders, especially bingeing, are
associated with later overweight and gaining weight could promote the clinical
expression of a polycystic ovary syndrome. The emergence of these disorders is
mainly the consequence of several promoting factors acting during infancy, pubertal
development, and early adolescent years. The knowledge of different pathogenic
and risk factors is important to orient the history taking. Various studies have put in
evidence the possible genetic transmission of vulnerability to ED, so girls coming
from family where restrictive disorders or bingeing or struggling for being over-
weight are common are at risk for unhealthy relation with feeding. Recent
8 Eating Disorders in Adolescence 133
Table 8.1 DSM5 criteria for ED

Anorexia nervosa (AN) Persistent restriction of energy intake leading to
significantly low body weight.
Intense fear of gaining weight or of becoming fat or
persistent behaviour that interferes with weight gain.
Disturbance in the way one’s body weight or shape is
experienced, undue influence of body shape and weight on
self-evaluation, persistent lack of recognition of the
seriousness of the current low body weight.
Bulimia nervosa (BN) Recurrent episodes of binge eating: eating, in a discrete
period, an amount of food that is definitely larger than most
people would eat with a sense of lack of control over eating
during the episode.
Recurrent inappropriate compensatory behaviour to prevent
weight gain (self-induced vomiting, misuse of laxatives,
diuretics, or other medications, fasting, or excessive
exercise).
Self-evaluation is unduly influenced by body shape and
weight.
Binge eating disorder (BED) Recurrent episodes of binge eating not associated with the
recurrent use of inappropriate compensatory behaviours.
Binge Eating Disorder is associated with more subjective
distress regarding the eating behaviour
Avoidant/restrictive food intake Persistent failure to meet appropriate nutritional and/or
disorder (ARFID) energy needs associated with:
Significant loss of weight or failure to achieve expected
weight gain or faltering growth in children
Significant nutritional deficiency
Dependence on enteral feeding or oral nutritional
supplements
Marked interference with psychosocial functioning
Other specified feeding or eating Atypical Anorexia Nervosa: all criteria are met, except
disorder (OSFED) despite significant weight loss
Night Eating Syndrome: Recurrent episodes of night
eating (…)
evidences pointed out the possibilities of epigenetic modifications occurring in the

intrauterine life or related to adverse events in childhood. Sexual abuse, maltreat-
ments, and neglect are frequent in the history of subjects with emotional feeding and
tendency to loss of control [3, 4]. The genetic background and the family climate
influence the development of typical personality traits that in subjects with tendency
to restrictive eating are shyness, insecurity, cognitive rigidity, perfectionism, and
respect for rules. In subjects with tendency to bingeing, depressed mood, low self-
esteem, high stress reactivity are described. The comorbidity with anxiety disorders
is elevated in all the cases. The increase of steroid hormones in post-pubertal years
seems to facilitate the clinical expression of ED, with a critical peak between 13 and
17 years. Social pressure on thinness and fitness play a major role in the spread of
attention to body image and caloric control. The current feminine dominant models
ever-present in the messages of the mass media and the social networks magnify the
difficulties with the changes of body image typical of adolescence.
Activation of:
CRH-ACTH-cortisol
AVP- Autonomic nervous system
GhRH inhibiting hormone?
Peripheral adaptation to low
energy intake
Vagus nerve
GnRH
Nutrients
endocannabinoids Oxytocin
LH Ghrelin
Leptin
adiponectin
Insulin
Amylin
CCK
GLP-1
PP
PYY
Adipose tissue
Gastrointestinal tract
Fig. 8.1 Simplified overview of peripheral signs of energy availability to hypothalamic centres
The hypothalamus-pituitary centres are highly sensitive to energy availabil-

ity. The evolution in all living beings has selected homeostatic mechanisms to
avoid reproduction in circumstances at risk of failure. In humans, several sophis-
ticated feedback mechanisms (Fig. 8.1) link growth, pubertal maturation, and
menstrual function to signals coming from fat, GI tract, and stress response
activation, in order to consent ovarian activity only when a metabolic equilib-
rium is present [5–7]. The same mechanisms, with similar thresholds, control
the neo-apposition of bone mass and consequently reduce bone turnover.
Oestrogen deficiency and hypercortisolism promote bone resorption. Physical
hyperactivity, use of SRIs, specific nutritional deficiency, and genetic predispo-
sition are additional pathogenic factors. These adaptive repercussions of energy
deficiency are particularly evident in very young girls during puberty or in the
first years of gynaecological age [8].
For the following hormones, a key role in response to food restriction is well
documented in human beings:
1. Leptin a protein hormone [9] produced by adipocytes in a pulsatile fashion regu-

lates food intake at hypothalamic level stimulating the production of anorexi-
genic hormones (NPYY, ARP) and indirectly inhibits the production of GnRH
during pubertal maturation (threshold effect) and during the fertile period of life.
This hormone displays multiple regulatory functions on ovarian folliculogenesis,
bone marrow, bone turnover, and on liver triglycerides metabolism.
2. Ghrelin an orexigenic peptide [10] produced by specific cells in stomach and duo-
denum increases hunger and stimulates food intake. It acts on neuropeptide NPY
and, unlike many other endogenous peptides, is able to cross the blood–brain
barrier. Moreover, Ghrelin produced inside the CNS, stimulates growth hormone
and is involved in stress reaction; the peptide is also a stimulus on osteoblasts
formation.
3 . Insulin [11] the protein hormone produced by endocrine pancreas, besides the
well-known effects on glucose cell uptake and fat deposition, acts at hypotha-
lamic level as a sign of energy availability and is involved in the gratification
related to food experience.
Other gastrointestinal peptides (PP, GLP-1, amylin, PYY), oxytocin, produced

by neurohypophysis but not exclusively, endocannabinoids, adiponectin, and vari-
ous nutrients (glucose, specific amino acids, long chain fatty acids) all interact [12]
in the signalling of energy status to CNS. The adaptive response to energy defi-
ciency is mainly based on:
1. The activation of autonomic nervous system, comprehensive of secretion of

adrenalin by adrenal medulla, with imbalance of the sympathetic/parasympa-
thetic physiological equilibrium (mainly reduced sympathetic/exaggerated para-
sympathetic nervous system activity)
2. The increased activity of CRH-ACTH-cortisol axis as a trigger of stress reaction,
a modulator of behavioural and metabolic adjustments, an inhibitor of GnRH
activity and of bone reabsorption
3. The reduction of peripheral conversion of thyroxine in 3-jodo-thyronin (FT3 the
bioactive form) in peripheral tissues
4. The uncoupling at hepatic level between Gh stimulus and IGF-1 production; the
reduced IGF-1 concentrations slow down all mitotic processes in the body.
8.2 Diagnostic Work-Up
The assessment of an adolescent with suspected ED should start with a comprehen-

sive history and a complete physical examination.
The history should focus on:
• Psychiatric disorders, weight concern, or food habits in the family

• Family conflicts or difficulties in recognizing and managing emotions
• Growth and nutritional problems in infancy
• Previous overweight and recent weight changes
• Stress, depression, or bereavement
• Perfectionism, obsessive traits
• Selective eating
• Functional or painful gastrointestinal disorders
• Diseases requiring food control (diabetes, coeliac disease…)
• Quality and quantity of physical activity
• Body reaction to cold (Raynaud phenomenon)
• Recent fainting fits
• Use of drugs or nutritional supplements
The physical examination can also be perfectly normal if the ED is at its begin-
ning, but it is important to check, just with a handshake, the finger temperature, to
consider the dryness of skin appendages, to look at the clothes (if baggy or layered).
The signs of autonomic dysregulation are rather precocious: bradycardia, ortho-
static hypotension.
The measurement of BMI is the starting point of body evaluation, but even if
18.5 has been proposed as a cut-off for menstrual function, this figure is only
approximate. If the history does not give clear evidences, it is useful to propose an
evaluation of body composition. A rapid, non-invasive and relatively low-cost
method of orientation is the BIA. The technique determines the body tissue electri-
cal impedance, which can be used to calculate an estimate of Total Body Water
(TBW) and to derive Fat-Free Mass (FFM) and, by difference with body weight,
Body Fat (BF). It must be kept in mind that dehydration is a recognized factor
affecting BIA results and that moderate exercise before the measurements lead to an
overestimation of fat-free mass and an underestimation of body fat percentage; an
extremely reduced BMI is another limit to application of this method. BIA has a
good accuracy in the prediction of resting energy expenditure (REE), the esteem of
the energy required from the body in 24 h, always reduced as adaptation to negative
energy balance, traditionally measured by calorimetry. As additional assessment the
BCM, the measure of metabolically active body cells inside FFM, indexed to height,
if lower than seven is a clue of catabolic phenomena. BIA (and BCMI) is also very
useful for tracking body composition in an individual over a period [13, 14].
The US scan points out the degree of functional regression of internal genitalia.
Reduced uterine size and endometrial thickness reveal the hypo-oestrogenization.
Ovarian structure is often multifollicular (Fig. 8.2) in response to adaptation to
reduced energy availability or during weight recovery. In situations of serious
energy deficiency, the ovaries may appear compact; liver steatosis, evident as a dif-
fuse increased echogenicity, is also often present due to the accumulation of triglyc-
erides within hepatocytes. In anorexia nervosa can be useful to control the kidney to
exclude a nephropathy linked to hypokalaemia and malnutrition.
Fig. 8.2 Multifollicular
ovary (slightly increase
volume, multiple follicles
of diameter >8 mm,
without stroma
visualization)
Routine blood tests can be normal if the metabolic situation is not particularly
compromised; alterations are present when catabolic processes take place: an
increase in albumin with a decrease in globulins, a relative increment in creatinine
and liver enzymes, especially SGOT. A reduction in white blood cells and erythro-
cytes is present when the medulla function is impaired. Total cholesterol can be
elevated because of mobilization of fat stores; high ferritin concentrations are a
marker of inflammatory status. In special conditions, specific nutritional markers
can be tested as retinol binding globulin and transferrin. The monitoring of plasma
electrolytes is mandatory in case of suspect of purging behaviours (vomiting or
laxative abuse) or during weight rehabilitation, together with amylase dosage.
Standard urine analysis can show higher concentrations linked to dysregulation of
ADH with altered osmoregulation.
The endocrine profile is typical of functional hypothalamic amenorrhoea, with
low LH levels, normal FSH and, if tested, estradiol levels near the lower range.
Prolactin is in the normal–low range and AMH is normal, as follicular reserve is
intact. For diagnostic purpose, the profile of hormones involved in metabolic adap-
tations is more discriminating. Plasma levels of FT3, IGF-1, insulin (testing glucose
concentrations at the same time) are generally reduced, while IGFBP 1 and 2 and
SHBG are increased. Cortisol production is always increased, but the elevation is
more evident if blood sample is collected in the late afternoon or using salivary
assay at awakening [15]. The measure of Ghrelin and leptin is rarely disposable in
clinical practice.
As previously mentioned, the adolescents with restricted eating experience a
reduction in bone mass within 6–8 months; there is a preferential loss of trabecular
bone which is more metabolically active and has a higher turnover, evident at the
lumbar spine, but also cortical bone is involved. In pre-pubertal adolescents, ED can
cause interruption of linear growth with reduction of bone size accrual. Therefore,
an evaluation of bone mineral density is useful to control eventual bone loss. The
lumbar spine and total body less head are the preferred skeletal sites for performing
BMC and areal BMD measurements. In this age group, we refer to the Z-score,
using a specific reference derived from a young, race, and sex-matched population.
In girls with growth delay, the spine and total body BMC and BMD should be
adjusted using the height Z-score or for spine using the volumetric BMD. In sub-
jects with serious malnutrition too, the reduced periosteal bone apposition impair
the vertebral body volume more than the area, requiring similar correction. Lean
mass hypo hydration could be another variable affecting the measurement. Soft tis-
sue measures (body fat and lean body mass) derived from whole body scans may be
helpful for an evaluation of body composition more accurate than using BIA:
according to guidelines, lean mass can be better estimated using appendicular lean
mass divided by height square (ALMI) using specific Z-score [16].
Quantitative ultrasound bone evaluation is primarily a research technique and the
results in this population are higher than in controls and unrelated to DXA measures.
Nail fold video-capillaroscopy is sometimes useful to distinguish hyperactive
arteriovenous anastomosis due to adaptive response to energy deficiency from pat-
terns related to connective tissue disorders.
8.3 Therapeutic Management
Menstrual dysfunction is sometimes the first sign of an eating disorder, especially

when the restriction of food intake is not dramatic. Bulimia nervosa is more difficult
to recognize because the repercussions on endocrine equilibrium are fainter; but the
need for early diagnosis is anyway present for the high comorbid rates of mood dis-
orders and suicidality. Therefore, the ability of the gynaecologist or the paediatrician
that meet the girl to identify the real problem is paramount. The first rule is to leave
enough time for listening to both the parents and the daughter, preferably not together.
When a clear diagnosis is made, it is important to find the words to explain the
relationship between nutritional state and amenorrhoea as a sign of loss of equilib-
rium and to motivate the girl to start a therapeutic plan.
The management of an ED should always be multidisciplinary and co-ordinated.
Weight restoration is the main therapeutic objective [21]. Nutritional advice and
counselling can be the first step when the feeding control and the psychosocial
impairment are not extreme, with ongoing medical monitoring. Outpatient support-
ive psychological counselling for the girl and, eventually, for her caregivers is gener-
ally advisable. For younger patients, family therapy and interventions are proposed.
In subjects with AN or significant nutritional deficiency or with frequent binge
eating and purging, different levels of care are required. An initial assessment of the
severity of the health repercussions of the disorder can require the cooperation of
other physicians [17]. A cardiologic evaluation is generally necessary when the
weight loss is significant, for the risk of precocious functional anomalies, as a mini-
mal reduction of the heart output, a lengthening of QT, arrhythmia due to electro-
lytes disturbance, and secondary mitral valve prolapse. Severe physical and
psychiatric conditions may suggest hospitalization (Table 8.2); intensive treatments
in a residential facility or day treatment programmes in a specific ED Unit can be
therapeutic options in less severe situations. We refer to specific references for the
discussion of efficacy of treatment [18–20].
Reaching and maintaining a target weight (around 20–25th BMI percentile for
age and for specific population) restoring physiological body composition is a fun-
damental step for the return of menses; subjects previously overweight need prob-
ably higher weight goals [22]. Metabolic hormones (FT3, IGF-1, cortisol) levels in
the normal range are generally a prerequisite.
The bone mass restoration is a slower process and requires long time of follow-
up (more than 1 year) to be detectable [23]. Situations of partial weight recovery
with irregular menses and bone density long-lasting deficiency are quite frequent.
Moderate bone-loading exercise after a certain weight rehabilitation can be useful.
It is still a matter of discussion the opportunity to treat adolescents with hypo-oes-
trogenism related to energy deficiency with hormonal or non-hormonal treatments,
mainly to contrast bone loss. In Table 8.3, we synthetized the therapeutic proposal
and their results.
Moreover, few data point out that oestrogen substitution may facilitate response
to psychiatric or pharmacological interventions [29], beyond its positive effects on
urogenital atrophy. According to the current state of knowledge, oestrogen therapy
Table 8.2 Indications • BMI ≤ 75% for age

supporting hospitalization in • EKG serious abnormalities
a girl with ED • Severe bradycardia and hypotension
• Dehydration
• Electrolytes disturbance
• Hypoglycemia
• Hypothermia
• Infections
• Uncontrolled vomiting
• Acute complications of malnutrition: syncope, seizures,
pancreatitis …
• Food refusal
• Uncontrollable bingeing and purging
• Severe depression, suicidal ideation
• Necessity to be far from family
• Comorbid psychiatric conditions
• Failure of outpatient treatments
Table 8.3 Proposal for therapeutic options for contrasting bone loss in ED
Treatment Efficacy and remarks Reference
Combined hormonal contraceptives As monotherapy not effective on Golden et al.
(20–35 mcg EE) prevention of bone loss [24]
DHEA 50 mg/day More effective in association with DiVasta et al.
oestrogens or oestroprogestin [25]
Recombinant Human IGF-1 Effect dose dependent: 30 mcg/kg × 2 Grinspoon
effective on markers of bone formation et al. [26]
100 mcg/kg × 2 effective on markers of
bone formation and resorption
Calcium and vitamin D Effective only in case reports
supplementation
Alendronate 10 mg/day Associated with calcium and vitamin D; Golden et al.
effective but weight restoration remains [27]
a significant variable. Reserve for
long-term safety in young people.
Physiological oestrogen-progestin Transdermal estradiol therapy seems Misra et al.
replacement therapy: 100 mcg E2 more effective than oral, probably [28]
patch twice weekly + MPA 2.5 mg because of the lack of suppression of
12 days every month hepatic IGF-1 synthesis. The bone
catch-up in not complete.
alone cannot correct the multiple factors contributing to bone loss in subjects with
energy deficiency, substituting to the effect of weight recovery. In few cases, it may
provide a sense of reassurance because the patient has regular menstrual period and
feels protected against osteopenia, which may reduce the efforts to rehabilitate her
weight.
In conclusion, oestrogen-progestin replacement or physiological puberty induction
in younger girls, with low dosages and always using transdermal estradiol, can be
options to consider, if prescribed in agreement with the psychologist caring for the girl.
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Diagnosis of Polycystic Ovarian
Syndrome in Adolescence 9
Anna Maria Fulghesu, Cristina Porru, and Elena Canu
Abbreviations
A Androstenedione
AES Androgen Excess Society
AFC Antral follicular count
CAH Congenital adrenal hyperplasia
FAI Free Androgen Index
FNPO Follicle number per ovary
FNPS Follicle number per ovarian scan identified as a median
MFO Multifollicular ovary
NIH/NICHD National Institute of Health/National Institute of Child Health and
Human Development
OGTT Oral glucose tolerance test
PCOM Polycystic ovarian morphology
PCOS Polycystic ovarian syndrome
S/A Ovarian area in median section (A) and stroma area in the same
picture (S)
T Testosterone
US Ultrasound
A.M. Fulghesu (*) • C. Porru • E. Canu

Dipartimento di Chirurgia, Università degli Studi di Cagliari, Cagliari, Italy
Reparto di Ginecologia ed Ostetricia, Policlinico Duilio Casula, Monserrato, Cagliari, Italy
e-mail: [email protected]; [email protected]; [email protected]

144 A.M. Fulghesu et al.
9.1 Introduction
The Polycystic Ovarian Syndrome (PCOS) is the most common endocrinopathy in

the female population, interesting 5–10% of women during childbearing age.
The clinic manifestations are very heterogeneous, with rare or absent ovulatory
cycles, leading to oligoamenorrhea, and hyperandrogenic signs as acne, seborrhea,
alopecia and hirsutism [1].
Often are present also metabolic alterations, often independent by obesity, char-
acterized by insulin resistance and/or hyperinsulinemia and tendency to put on
weight. In certain cases, where insulin levels are particularly elevated achantosis
nigricans is also present [2].
The pelvic ultrasound (US) shows big ovaries, multiple follicles (n > 10) of small
size (average diameter 2–8 mm) arranged in the subcortical seat around a hyper-
echogenic stroma and with enlarged volume ovaries (>8 ml), in absence of domi-
nant follicle [3].
The complexity of the syndrome depends from the fact that clinical features are
variable, mild, or serious, depending from the age, differently evolving, differently
influenced by lifestyles and diet-styles.
From the definition of the first authors, Stein and Leventhal [4], which in 1935
had discovered the existence of a precise association between some clinical ele-
ments (infertility, amenorrhea, hirsutism and obesity) and the morphology of the
ovaries: increased volume and pearly appearance and texture, many other defini-
tions have been proposed; the two main used by authors in the last 20 years are those
of the NIH/NICHD (National Institute of Health—National Institute of Child Health
and Human Development) of 1990, that of the Consensus of Rotterdam 2003 [5],
and the last of Androgen Excess Society (AES) [6].
The definition proposed by NIH/NICHD envisages the presence of clinical
hyperandrogenism or hyperandrogenemia, oligo or anovulation and the exclusion
of other disorders that cause hyperandrogenism, as congenital adrenal hyperplasia,
androgen secreting neoplasms, hyperprolactinemia, and thyroid dysfunction.
This definition excludes altogether the use of ultrasound in diagnosis and this
view was not shared by many authors.
In 2003, the Consensus of Rotterdam [5] has reasserted the importance of ovar-
ian morphology to the diagnosis of PCOS.
The consensus introduces the diagnosis of PCOS when there is the presence of
at least two of the following symptoms (excluding other causes of
hyperandrogenism):
• Oligoanovulation (oligoamenorrhea)
• Clinical hyperandrogenism and/or biological hyperandrogenemia
• Polycystic ovary morphology at ultrasound
More recently, the Androgen Excess and PCOS Society [6] proposed the hers
guidelines which require the presence of:
9 Diagnosis of Polycystic Ovarian Syndrome in Adolescence 145
• Hyperandrogenism biochemical and/or clinical

• Presence of chronic anovulation
• Polycystic ovarian morphology
• The exclusion of other disorders that cause hyperandrogenism
From “consensus,” therefore, ovarian ultrasound evaluation becomes a crucial

stage in the diagnostic workup, and the introduction of endovaginal probes with
always best sharpness of the image has made it possible to study more precisely
both the size and the ovarian morphology even in obese patients, in which the trans-
abdominal scan was not sufficiently reliable.
On the other hand, all these lead to increased detection of PCOS compared with
that found using the criteria of the NIH from 18 to 9% [7].
The real belonging to the large category of patients with PCOS of the last two
phenotype, patients with anovulation and PCO ovary but without signs of hyperan-
drogenism, and patients with PCO ovary and hyperandrogenism but with normal
ovulatory cycles, has done and is doing much to discuss.
A work published by Belosi, Fulghesu, Lanzone et al. [8]. has reclassified the
population of patients for whom was made the diagnosis of PCOS by applying sepa-
rately the two diagnostic criteria. Of 375 patients studied, 345 comply with the cri-
teria Rotterdam and, of these, 273 also meet the criteria of NIH in 1990. Thus, there
are 72 patients who have a diagnosis based solely on the Rotterdam criteria. For
comparing the clinical and hormonal characteristics of these patients, it can be seen
that the 72 “non-NIH” show BMI, androgens, and insulin to lower that patients
“positive NIH.”
Another study by Welt et al. [9], which analyzed the hormonal characteristics of
PCOS patients, showed that patients NIH criteria negative (patients with menstrual
irregularities and PCO) had levels of testosterone and androstenedione similar to
that of the controls, and significantly lower than the two groups of patients affected
by hyperandrogenism + menstrual dysfunction or hyperandrogenism + polycystic
ovarian morphology (PCOM).
The diagnosis of PCOS still represents a research field for ultrasonographers,
gynecological endocrinologists, and pediatricians, and represents a big problem in
adolescence where apparently similar symptoms to those encoded as PCOS may
represent evolutionary stages of sexual maturation.
In this chapter, following elements for PCOS will be discussed in relation to
adolescence:
• Ultrasound
• Clinical symptoms
• Hormonal characteristics
• Metabolic aspects
We will examine the role of the distinct components of the syndrome in adoles-
cence to discuss if adult diagnostic criteria are workable at a young age.
9.2 Ultrasound
For more than 15 years sonographic criteria which become more frequent reference
to define the polycystic ovary was heavily influenced by the definition of Adams
et al. [10]: multiple follicles (n > 10) of small size (average diameter 2–8 mm)
arranged in the subcortical seat around a hyperechogenic stroma and with enlarged
volume ovaries (>8 ml).
There is, nowadays, a paucity of data for ovarian morphology for normal and
PCOS adolescents.
In 2003, the Consensus Conference of Rotterdam [5], after careful consideration
of the studies in the literature, introduced the following sonographic criteria for the
identification of PCO:
• Presence of at least 12 follicles in each ovary: the calculation must take account
of all the follicles present, from the inner edge to the outer one, irrespective of
their arrangement and, for a more exhaustive study, must evaluate different sec-
tions obtained on different planes.
• Follicular diameter between 2 and 9 mm: the follicular diameter corresponds to
the average of the measured diameters in the three sections, or to the diameter of
the follicle in the scan which appears circular.
• Increased ovarian volume (>10 mm3): for the calculation of the volume, various
formulae have been proposed, based on the preliminary identification of the three
diameters; software of modern ultrasound devices are capable of performing pre-
cise calculations (we generally recommend the use of the ellipsoid formula
P/6 × (D1 × D2 × D3)).
• Even the mere presence in a single ovary of one of the characters described
above constitutes a sufficient element for ultrasound diagnosis; otherwise ovar-
ian cysts presenting pathological look are excluded from the diagnosis. The
ultrasound examination should be also carried out in accordance with certain
specific rules:
• The operator must have performed a sufficient training to ensure the careful eval-
uation of clinical picture and the correlation with the given endocrinology.
• Whenever possible, the transvaginal ultrasound should be preferred especially in
obese patients.
• In women with regular menstrual cycles, the examination must be carried out in
the early follicular phase (3rd–5th day); in oligo-amenorrheic women you can
choose a random day or prefer the first 3–5 days following a bleeding induced by
progesterone. This type of timing guarantees the optimal approach for the quan-
titative assessment of ovarian volume and area.
• If there is evidence of a dominant follicle (>10 mm) or of a corpus luteum, the
ultrasound should be repeated in the next early follicular phase.
In clinical practice, for a proper diagnosis, mainly three aspects must be

evaluated:
• Ovarian volume
• The dimension, number, and arrangement of follicles
• The evaluation of the stroma.
Ovarian volume is increased in PCOS. Technical volume assessment seems pos-

sible by both transvaginal and transabdominal route. Since the ovarian surface is
irregular, the measurement of its volume as an ellipsoid is only approximate. The
ovary should be visualized and measured in all three planes (longitudinal, sagittal,
and transverse). Currently available ultrasound systems enable the assessment of
ovarian volume by marking the outlines and calculating the result using appropriate
software. Ovarian volume is traditionally calculated with a formula for an elongated
ellipsoid (π/6 × the highest size in each of the three planes). Since π/6 = 0.5233, it
is also possible to use a simplified formula: 0.5 × the highest size in the longitudinal,
sagittal, and transverse view) [11].
The recommended cutoff in 2003 has not changed over the years, the threshold
value of 10 cm3 has found general agreement among the various authors, even if the
same group who had proposed in 2003 [12], in 2005 he proposed to reduce to 7 cm3
the threshold value [13], while in 2013 the value of 10 is confirmed in the use of new
technologies [14].
Ovarian volume changes over time. The highest values are observed in adoles-
cents (1.3–3.8 years after menarche). Subsequently, this parameter gradually
decreases [15].
The available studies indicate that ovarian volume does not change much between
the age of 20 and 39 [14]. The results presented prove that there are natural, age-
related changes in ovarian volume, which should be taken into account when diag-
nosing PCO in adolescents.
Three-dimensional ultrasound is a recognized diagnostic modality to assess
ovarian volume. The mean volume in adult patients with PCOS ranges from 10.6 to
16.7 ml, whereas healthy women present values ranging from 5.2 to 8.7 [16]. The
comparison of ovarian volume measured in two- and three-dimensional images has
been the subject of numerous studies [7]. However, at present few data are present
in adolescence [17].
As for the number of follicles the cutoff proposed in 2003 varies from 10 to 12
but detected on only one ovarian scan identified as a median (FNPS).
With the advance of US technology, recent guidelines, largely based on two stud-
ies in adults, recommended that the US features diagnostic for PCOM will be modi-
fied increasing the threshold of follicle number to 25 per ovary (FNPO), scanning
by TV transducer frequency >8 MHz, and counting by a specific software but, per-
haps, because of the low availability of such probes and software, this cutoff is
disregarded in the clinical practice. From the results proposed as the basis for the
guidelines, 10 ml would be confirmed as the best cutoff for FNSP realized in median
ovarian section, with a sensitivity and a sensitivity equal to 81 and 84%,
respectively.
The authors, however, suggest to apply these rules only above 18 years, and only
if you have a probe of 8 MH, and suggest to stick to only ovarian volume in the other
cases [14].
Another method of calculating and assessing follicles is the system enabling
three-dimensional reconstruction with marking fluid-filled spaces (e.g., VOCAL,
SonoAVC) [18].
In adolescence, the problem is more present because the follicular count may be
difficult to do in TA ultrasound, and, often, the follicle number may be increased,
than cutoff for adult, leading to overdiagnosis when applied to young girls [19, 20].
So that the workable parameter in the diagnosis of PCOS in adults could not be
reliable in very young subjects.
About the follicle size, recent studies point out that the follicles including
between 2 and 5 mm are more characteristic of the syndrome and more related to
the presence of clinical symptoms [7]. The small size of the antral follicles reflects
the arrest of follicular maturation. The description of the arrangement, even though
impressive, is not reflected in the guidelines.
Figure 9.1 represents the classic PCOM morphology.
However, following these criteria, to have a polycystic ovarian morphology
(PCOM), could happen to a 24% of women in the reproductive life, and this per-
centage could be doubled in adolescence [21], and do not permit to overcome very
important diagnostic difficulties.
Fig. 9.1 The PCO morphology is characterized by the increased ovarian volume, by the increased
number of follicles, by their peripheral arrangement, and by their small diameter
Our recent data on 302 healthy adolescents demonstrated that PCOM is present
in 43% of group but is present in the 76% of them in the first 3 years from
menarche.
After 3 years, this proportion is very different: disappears physiologically in 40%
of subjects decreasing to 38%, whereas such morphology persists only in the 22%
of girls after 5 years of menstrual cycle, which presumably could represent the sub-
jects at real risk for menstrual dysfunction or PCOS (Fulghesu AM submitted for
publication).
The spontaneous evolution versus the normal ovarian morphology suggests that
PCOM in this age represents a developmental step in ovarian function.
Other US aspects, as increased ovarian stroma and higher stromal blood flow,
whereas accepted as significant predictors of hyperandrogenism [22, 23], are not
suggested in the official guidelines for the diagnosis of PCOM, but could be helpful
in identifying the syndrome.
Indeed, excluding the evaluation of the ovarian stroma, it excludes the parame-
ters that were already considered the most specific to the strong correlation with the
circulating androgens [24]. In particular, in 1985 Adams and coworkers had reported
the peripheral disposition of the follicles in the ovary PCO around a hyperechoic
stromal tissue core. Dewailly observed that the choice of studying the ovarian
volume is due to the fact that this parameter not only is easy to measure, but is also
directly correlated with the hypertrophy of the stroma, of which discouraged the
direct evaluation because it was considered subjective and difficult [25, 26]. For
these reasons in recent years numerous studies have been undertaken to improve the
diagnostic US specificity mainly focusing on evaluating stromal hyperplasia.
Various systems have been proposed to define the increase of representation and
echogenicity of stroma, normally slightly lower than that of the myometrium. None
of these proposals has had large following because it is considered a highly subjec-
tive evaluation and operator-dependent instrumentation.
In 2001, my group has evaluated the measure of stroma compared to the remain-
ing ovarian parenchyma, measuring the picture corresponding to the maximum
ovary planar section, the area of the central stromal thickening zone (drawing
obtained the peripheral profile of the stroma with caliper) and the total area of the
ovarian parenchyma (drawing obtained with a second caliper, the outer limit of
organ) and then calculating the ratio (S/A) (Fig. 9.2) [27].
With this kind of evaluation the diagnosis of ovary PCO corresponds to values of
S/A > 0.34, more than a third of the ovary area in the median section (Fig. 9.2).
A subsequent multicenter study [24] indicated the S/A ratio, is gettable by stan-
dard technology, without inter-operator variations and provides great sensitivity and
diagnostic specificity (96%). This index closely correlated with the plasma testos-
terone (R 0.731 p < 0.001) or/and androstenedione (R 0.734 p < 0.001).
The adoption of this new parameter finally could lead to a precise differentiation
of PCO ovary already named multifollicular ovary. The multifollicular pattern
(MFO) is described by several authors as an evolutionary step in adolescence [28]
or as pathognomonic of amenorrhea or oligomenorrhea [29]. Such situations, from
the pathogenic point of view, are characterized by gonadotropin pulsatility
Measuring the ovarian S/A ratio
S/A = 0,41
Fig. 9.2 A proportion between the ovarian area in median section (A) and stroma area in the same
section (S), S/A ratio is obtained from two measures given by caliper
Measuring the ovarian S/A ratio

S/A = 0.11
Fig. 9.3 A proportion between the ovarian area in median section (A) and stroma area in the same
picture (S), S/A ratio is obtained from two measures given by caliper. Ovary PCOM in not PCOS
girl: S/A 0.11
alterations due to eating disorders, or strong physical or psychological stress [10,

30] (Fig. 9.3).
These secondary amenorrhea are frequent in young age (adolescents often
stressed and with mild eating disorders (DCA)), but with no signs of hyperan-
drogenism. This disorder is increasing and can be associated with normal BMI in
the presence of conflicting attitudes towards food.
Other authors [16, 31, 32] confirmed the importance of S/A stroma in diagnosing
PCOS. Battaglia and Sun found out exactly the same S/A ratio cutoff respectively
in 3D and transrectal US studies, and, recently, the S/A ratio demonstrated the best
US PCOS diagnostic performance when associated with Total Ovarian Follicular

count (FNPO) [33].
The increased stroma, until now, is studied mostly in adult population, for the
difficult evaluation in TA. Further studies could confirm this possibility, considering
that technical probe and software amelioration could overtake the problem of the
TA US approach.
9.3 Additional Diagnostic Perspective
In recent years, to try to improve the ultrasound diagnosis of PCO, the application
of color Doppler in the transvaginal US was studied in ovarian and uterine vessels
highlighting an increase of pulsatily index of the uterine artery for effect of high
levels of androgens and a reduction of uterine perfusion [33].
Subsequently the focus shifted on the vessels of the ovarian stroma noting the
association between high levels of LH and increased stromal vascularization with a
decrease of the intraovarian resistances and consequent stromal hyperplasia in
patients with PCOS pattern [22].
Higher stromal blood flow, whereas accepted the significance as predictors of
hyperandrogenism, actually is not suggested in the diagnosis of PCOS [7].
On the other hand, PCOS subjects presented increased Anti-Mullerian Hormone
(AMH) levels [34, 35]. The number of follicles at all growing stages especially pre-
antral and small antral follicles is increased in PCO. Thus elevated serum AMH
level, as a reflection of this follicular stock, is two to fourfold higher in women with
PCOS than in healthy women [35, 36]. Given its strong implication in the patho-
physiology of PCOS, serum AMH had been considered the “Gold Standard” in the
diagnosis of PCOS. Even though serum AMH would be theoretically more accurate
than antral follicular count (AFC), as it reflects also the excess of small follicles
non-visible on ultrasound [37], it is considered premature to make this diagnostic
transition.
The robust association between AMH and AFC has led some authors to insert
their performance in the diagnosis of PCOS [38], but it is found in all PCOM popu-
lations also in absence of hyperandrogenism [39].
In conclusion, therefore, we can say that the diagnostic ultrasound of PCOS can-
not ignore the rules established in Rotterdam in 2003, which at present constitute
the major criteria for identification of PCOS ovary; however, these guidelines are
difficult to apply during the first 5 years after menarche when the physiological
PCOM presence can reach 2/3 of the subjects.
9.4 Clinical Criteria
When PCOS is suspected in adolescence, a collection thoughtful and careful of

medical history will be very useful for verifying the durability and authenticity
of the described symptoms, and identify the presence of risk factors for PCOS
and insulin resistance as by low birth weight “sine causa,” big weight gain in the
first year of life, and finally pubarche premature and/or precocious puberty
[40, 41].
Irregular menstrual cycles with oligoanovulation or secondary amenorrhea, is a
very frequent symptom.
This event is to be considered normal in the first years after menarche, and is
shrinking gradually from 2 to 3 years of gynecological life in normal girls,
while it can stabilize with the passing years in individuals suffering from
PCOS [42].
This clinical sign is present also in a great number of subjects stressed, athletes,
too lean, or suffering from some form of eating disorders, as orthorexia, which pre-
sented menstrual dysfunction for alteration of gonadotropin secretion. For this rea-
son, it is important to evaluate the lifestyle of subjects [43].
In adolescence, even the classic clinical criteria of hyperandrogenism such as
acne, hirsutism, and alopecia should be considered with a different approach.
In fact, acne is a teenage phenomenon, physiological in both sexes. Its onset fol-
lows the adrenarche and adrenal androgen production, and physiologically tends to
shrink after 2–3 years after menarche, to disappear in 6–7 years. In subjects really
PCOS on the contrary, it is getting worse and as severity of injuries as an extension,
but especially no signs of spontaneous improvement, and returns to the suspension
of any treatment even up to 35–40 years [44].
On the contrary rarely hirsutism is a teenage temporary phenomenon. In fact, it
needs a long time of hyperandrogenism to become a real problem. It may have dif-
ferent etiologies in addition to PCOS, first of all adrenal hyperfunction by enzyme
deficiencies, but also a fair incidence of family forms.
For a correct assessment of hirsutism the Ferriman and Gallway [45] is the best
scale, identifying nine body areas where hair follicles are hormone-dependent, with
the exception of leg and forearm, where the familiar ethnic component is predomi-
nant. This scale assigns a value from 0 to 4 for each area and considers three levels
of severity depending on the score achieved: <8 not relevant; Mild from 8 to 14;
moderate 15 to 24; serious >24 (Fig. 9.4).
Hyperandrogenic alopecia is really rare in young girls, and the differential diag-
nosis with other familial forms or “sine causa” can be difficult. For this reason its
use in the diagnosis of PCOS in adolescence is marginal.
9.5 Endocrine Criteria
The endocrine assessment must include androgens assay. Androstenedione and

Testosterone, adrenal hormone 17OHP, and prolactin. Gonadotropins may be evalu-
ated in suspicion of hypothalamic–pituitary axis disorders for example DCA or
stress, or other primary ovarian disease.
Fig. 9.4 Assignment of hirsutism score
Classically, the syndrome was attributed to altered LH/FSH secretion. Recent

data have shown that the relative increase in the LH/FSH is only present in a minor-
ity of cases of PCOS [46], and does not alter either the prognosis or the therapeutic
approach [47, 48].
The estradiol assay can be useful only in that it indicates the presence of follicu-
lar activation.
Prolactin is essential in the differential diagnosis of anovulation due to
hyperprolactinaemia.
Ovarian androgens can be assessed only in early follicular phase, being involved
in the production of progesterone, and therefore always high during ovulatory and
luteal phase.
Often total testosterone (T) and androstenedione (A) are not so high in absolute
values, or only one rose above normal cutoff (A > 3.5 ng/mL, T > 0.7 ng/ml), as a
function of individual enzymatic pathways. Moreover, the dosage of the T is not
technically simple and can be unreliable. It would be useful to combine it with the
dosage of SHBG, which permits to calculate the Free Androgen Index (FAI) assess-
ment, which replaces the direct determination of free testosterone (FT). FAI is direct
active on receptors and is considered the most reliable marker of hyperandrogenism
[47].
Among the adrenal androgens the most important is the 17OHP, which allows
the exclusion of cases of classical and non-classical Congenital Adrenal Hyperplasia
(CAH) and, in case of clinical adrenal hyperfunction, DHEAS.
9.6 Metabolic Aspect
The incidence of obesity, metabolic disorders, diabetes type 2, and the presence of
metabolic syndrome was significantly increased in patients with PCOS [46].
Often the adipose tissue presents an android distribution, similar to an apple,
which is put on relation with both insulin resistance and hyperandrogenism [49] and
accounts for metabolic and cardiovascular disease. Obesity was observed in about
half of women PCOS during childbearing age [50] and is considered one of the
causes of insulin resistance and hyperinsulinemia.
Hyperinsulinemia, in response to food ingestion, however, affects also a 40–60%
of normal-weight subjects presenting normal fasting insulin levels [51]. It’s been
suggested that normal-weight women with PCOS are suffering from a form of insu-
lin resistance “intrinsic” to the syndrome while the obese patients present a state of
insulin resistance in part inherent to the syndrome, and, in part, determined by
increased body fat. Increased insulin secretion and peripheral insulin resistance may
coexist in a heterogeneous way depending on the BMI.
Hyper-insulin secretion may be different, from a pathophysiological point of
view, in lean and obese patients. From clinical observations in subjects presenting
low birth weight and premature adrenarche and showing insulin resistance in child-
hood and young age, some authors consider this state a risk factor for development
of PCOS at puberty [40, 41, 52].
In adolescence, fat deposits must reach 24% of the body mass to have menarche
[43], and from a metabolic point of view, it is linked to a functional development of
insulin resistance, which should be temporary and run out about 2 years after men-
arche. Often subjects with PCOS do not lose this metabolic characteristic and pres-
ent multiple endocrine, skin, and biochemical effect of hyperinsulinemia [44].
However, despite this metabolic factor it is universally recognized as an important
element of pathophysiology of the syndrome, to date it is not considered on
Guidelines on Metabolic diagnosis.
This diagnosis should be made with both the determination of insulin and fast-
ing glucose and HOMA calculation, which discloses peripheral insulin resistance
and is increased especially in presence of body fat excess, and glucose and insulin
under Oral Glucose Tolerance Test (OGTT) for evaluating the insulin response
after load [53], which may be present also in lean subjects. In adolescence we find
blood glucose curves almost always normal, in view of the large secretory capacity
of the pancreas, except in cases of severe obesity, whereas the increased insulin-
emic response to glucose load is present in 70–90% of obese and 50% of lean
subjects.
As regards the reference values of insulinemia, their interpretation is not easy;
curves of normality for age and perhaps for ethnicity would be the gold standard
[53], but the presence of values above 200 microU/ml is considered to be
diagnostic.
In adolescence early diagnosis of hyperinsulinemia and the eventual normaliza-
tion, with dietary interventions and insulin sensitizers treatment, can prevent the
onset of obesity and overweight in girls. The evaluation of hyperinsulinemia and

insulin resistance can drive in the choose of therapeutic interventions to prevent the
development of the metabolic syndrome [52].
Conclusions
Considering the psychological and clinical consequences of wrong diagnosis, in
the adolescence the existing guidelines for adults cannot be applied as such, but
some exceptions needed (Fig. 9.5).
The recommendations emerging are:
• Wait 2 years after menarche before making the diagnosis.

• Refrain from diagnosis in doubt to avoid the occurrence of anxiety and
depression.
• Evaluation of metabolic status in presence of obesity and/or hyperandrogenism.
• Early treatment of hyperandrogenic and metabolic symptoms also before the
diagnosis, in order to avoid psychological distress and long-time conse-
quences of hyperinsulinemia.
• Consider carefully the ultrasound data, trying to get them with the best equip-
ment, and use the TV when possible.
Based on these evidences I believe that we could improve, in predictive terms,

our diagnosis of PCOS by inserting, where possible, the US evaluation of the
stromal component (S/A index).
Proposed Criteria for the Diagnosis of PCOS in Adolescence:

Presence of menstrual irregularities
+
Diagnostic criteria for polycystic ovary

syndrome in adolescents
a Chronic anovulationb c
Criterion Hyperandrogenism Polycystic ovaries
Diagnosis of PCOS + + +
Diagnosis of PCOS probable but not confirmed + + -
Diagnosis of PCOS not possible during adolescence + - +
Diagnosis of PCOS not possible during adolescence - + +
Not PCOS + - -
Not PCOS - + -
Not PCOS - - +
PCOS, polycystic ovary syndrome. Carmina. The diagnosis of PCOS in adolescents. AM J Obstet Gynecol 2010.
a Hyperandrogenemia is primary criterion-acne and alopecia are not considered as evidence for hyperandrogenism-hirsutism may be
considered sign of hyperandrogenism only when it has been documented to be progressive:
b Oligoamenorrhea (or documented anovulation) has to be present for at least 2 years:
c Diagnosis of polycystic ovaries by abdominal ultrasound has to include increased ovarian size (>10 cm3).
Fig. 9.5 Shows the proposal of Carmina of 2010 [54]

Presence of clinical hyperandrogenism worsening after at least 2 years from

menarche, or biochemical hyperandrogenism in the absence of adrenal disease
+
PCO ovaries with stromal hyperplasia (S/A > 0.33)
The presence of two-thirds of the above characteristics will place a suspect to be

verified over time.
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Recommendations for the First
Prescription of Hormonal Contraception 10
in Adolescence
Floriana Di Maggio and Gilda Di Paolo
Abbreviations
BMD Bone mineral density

BMI Body mass index
CHC Combined hormonal contraception
DMPA Depot medroxyprogesterone acetate
EP Estrogen progestogen
HC Hormonal contraception
LARC Long-acting reversible contraception
LNG-IUS Levonorgestrel-releasing intrauterine system
OC Oral contraception
POP Progestogen Only Pill
SLE Systemic lupus erythematosus
STI Sexually transmitted infection
VTE Venous thromboembolism
It is becoming more and more important to discuss the issue of contraception for
adolescents, as national and international data have highlighted:
• The increasingly young age at which sexual intercourse begins

• The frequent lack of contraception during sexual debut (Table 10.1)
F. Di Maggio, M.D. (*)

Adolescents Service A.S.L.Napoli1Centro, Naples, Italy
G. Di Paolo, M.D.
Pediatric and Adolescent Service, Pescara and Teramo, Italy

162 F. Di Maggio and G. Di Paolo
Table 10.1 Risk factors in unprotected sexual intercourse

Young age at first sexual intercourse Poor personal planning
Short relationships Alcohol abuse
Lack of family cohesion and child monitoring Psychotropic drug abuse
Older male partner Binge eating
Poor school performance Depression
Table 10.2 Resistance to contracep- Insufficient information on how they work

tive use Difficulties in speaking about it with partner
Perception of a foreign body or something that is
“not natural”
“It won’t happen to me” thinking about pregnancy or
illness
• The rise in the pregnancy rate [1]

• Unchanged amount of abortions in adolescence [2]
• Increased incidence of STI [3]
10.1 Counseling
Contraceptive counseling is essential, during which it is often necessary to over-

come a more or less explicit resistance to the use of contraceptives (Table 10.2).
We need to ensure the appropriate timing and language when supplying informa-
tion on all the available contraceptive methods, with regard to their use, their addi-
tional benefits, and any side effects.
It is necessary to arrive at a shared decision.
We need also to have partner agreement; in these cases, the compliance is
longer.
The agreement of the mother (where involved) is also important.
The importance of double Dutch contraception (condom plus hormonal contra-
ception) should be stressed in the context of the prevention of STI.
To give more information about emergency contraception.
10.2 First Prescription
It is essential to fully investigate both family and personal medical history.

Family history:
Investigate:
Cardiovascular disease: ischemic stroke, myocardial infarction (MI)

Previous venous thromboembolism (VTE) <45 years *
Hyperlipidemia
Hypertension
10 Recommendations for the First Prescription of Hormonal Contraception 163
Autoimmune diseases
Migraine
*at least 2 first-degree family members with VTE is a contraindication to EP use;

grandparents should be included in the family medical history.
Other papers have pointed out that a family history from a female patient (mother
or sister), in which that patient has experienced a CHC or pregnancy-related VTE,
may further increase VTE risk in her female relatives [4].
There is no indication to screen thrombophilia on the basis of a risks/benefits
assessment [5].
10.3 Clinical Examination
10.3.1 Personal Pathological History
Investigate:
Current or previous illnesses *

Migraine
Autoimmune diseases (SLE, rheumatoid arthritis, thyroiditis, Sjogren syndrome,
celiac disease) **
Raynaud syndrome
Drugs in use (exclusion of interactions)
Current or previous behavioral binge eating
Depression
Smoking (negotiate reduction in number of cigarettes)
Recreational drug use (alcohol, vasoactive substances)
Lifestyle (physical activity, sedentary, etc.)
*thrombophilic diathesis is an absolute contraindication for CHC use.

**in these cases it is useful to test for antiphospholipid antibodies.
10.3.2 Gynecological History
Investigate:
investigate:
menstrual cycle
Dysmenorrhea
Hypermenorrhea to choose a therapeutic pill
Premenstrual syndrome
STI risk
Clinical examination:
Always check
Blood pressure recording, Weight, Height, and BMI

Evaluate hyperandrogenic symptoms: acne, seborrhea, hirsutism
Not essential:
Gynecological examination
Pap Smear *
Breast examination
These can be carried out in a subsequent checkup
* <21 years: do not perform cytological screening independently of first sexual

intercourse or risk behavior—ACOG 2012, US preventive services task force 2012,
Canadian task force on preventive Health Care 2012.
All women who have been vaccinated against HPV should still follow the screen-
ing recommendations for their age groups (The American Cancer Society Guidelines
for the Prevention and Early Detection of Cervical Cancer 2016).
10.4 Routine Laboratory Tests?
These are not recommended routinely as they do not contribute substantially to

CHC safety. If there is a family history of metabolic diseases, autoimmune diseases,
diabetes or dyslipidemias, then these can be carried out.
The expected advantages of the elimination of prescription blood tests are:
To improve access to effective contraception for the adolescent population

To separate screening procedures and contraceptive prescription
To dispel the widespread belief that contraception is hazardous for female health
Recommendations at first control after 3 months use:
To note side effects and/or problems

Verify proper use end stress instructions of use.
Check blood pressure.
Annual follow-up
Blood pressure monitoring

Body weight and BMI evaluation
Pelvic examination
Screening for STI*
Stress the importance of checkups or telephone calls any time in order to

discuss side effects or to change contraceptive method.
*Recommendations ACOG-4-2012: screening for STI every year or every new
partner.
10.5 Choice of Contraceptive
The options regard composition, means of administration, and system of drug

intake.
Composition:
It is possible to choose between combined contraceptive and progestin only. Use
of long-acting reversible contraception (subcutaneous etonogestrel or IUS with
levonorgestrel, DMPA depot medroxyprogesterone acetate injection) is strongly
recommended in adolescence for less risk of failure and greater compliance [6, 7].
Today we have several CHC that differ in progestin* or estrogenic** composi-
tion and they also (all) have noncontraceptive benefits. It is therefore important to
choose an individualized CHC, examining the blood loss and therapeutic effects or
suspicious clinical elements (overweight, migraine).
Way of administration: oral, transdermal, transvaginal, subcutaneous,
intrauterine.
System of drug intake: 21 days, 28 days, continuous. Association with placebo
pills for continuous use is probably simpler to use and facilitate compliance.
It is very important to point out:
Instructions for the correct use.

What to do if you forget the pill.
Interactions with other drugs, diarrhea, vomiting.
It is not advisable to interrupt administration of OC because of greater risk of preg-
nancy, more side effects in the first months or after 1 month interruption [8].
*Desogestrel, gestodene, drospirenone, Chlormadinone acetate, dienogest, levo-

norgestrel, norelgestromin, etonogestrel.
**Ethinyl estradiol, estradiol valerate, estradiol hemihydrate.
At the first prescription of HC, further information may be given regarding
noncontraceptive benefits.
Positive effects on:
Pelvic pain and dysmenorrhea

Spotting and/or heavy blood loss
Endometriosis
Premenstrual syndrome
Signs of hyperandrogenism (seborrhea, acne, hirsutism)
Functional ovarian cysts and benign ovarian tumors
Iron-deficiency anemia
Pelvic inflammatory disease
Ectopic pregnancies
Protective effects:
Epithelial ovarian cancer

Endometrial cancer
Colorectal cancer
… .. how can we enhance contraceptive compliance?

Discussing any doubts and describing possible side effects:
Spotting, oligomenorrhea, breast tension, weight gain….
On many occasions, the real reason for low compliance is a concern about health
and fertility in the future.
Moreover, several authors have pointed out the close relationship between side
effects and the nonrational perception of a major health risk [9].
Categories of medical eligibility criteria for oral contraceptive use
1. A condition for which there is no restriction for the use of the contraceptive
method
2. A condition for which the advantages of using the method generally out-
weigh the theoretical or proven risks
3. A condition for which the theoretical or proven risks usually outweigh the
advantages of using the method
4. A condition that represents an unacceptable health risk if the contraceptive
method is used
Category 1: Unrestricted use
• Age—from menarche *°
• Postabortion—immediately first and second trimester, and post-septic
• Non-migraine headaches—mild or severe
• Minor surgery without immobilization
• Severe dysmenorrhea
• Endometriosis
• Breast disease: benign breast disease or a family history of breast cancer**
• Anemias—thalassemia, iron deficiency
• Raynaud’s disease—primary without antiphospholipid antibodies
*we have no data on the effect of OC assumption and post-menarchal growth.

°data concerning effects on bone mass are not univocal (possible reduction effect
on bone mass growth in very young people, but there is catchup with interruption of
the treatment) [10].
WHO (2009) guidelines point out a relation between an estrogenic level (20 mcg)
and BMD (bone mineral density) lower then controls; on the contrary, if you use
higher EE levels, there are no differences.
**in hormonal contraceptive users with a family history of breast cancer, there is
no higher risk of breast cancer [11].
In girls with known BRCA1/2 mutations, there is a risk of earlier breast cancer
onset in the OC users but there is another positive effect in terms of reduced incidence
of ovarian cancer, [12] so an individual evaluation end possible use of POP is advised.
Category 2: The benefits generally outweigh the risks
Smoking—aged <35 years

Obesity—BMI ≥30–34 kg/m2
Family history of VTE in a first-degree relative aged ≥45 years
Major surgery without prolonged immobilization
Superficial thrombophlebitis
Migraine headaches—without aura in women aged <35 years
Vaginal bleeding—suspicious for serious condition before evaluation
CIN
Raynaud’s disease—secondary without antiphospholipid antibodies
Non-liver enzyme-inducing antibiotics
Category 3: The risks generally outweigh the benefits
Obesity—BMI 35–39 kg/m2
Family history of VTE in a first-degree relative aged <45 years
Immobility (unrelated to surgery)—e.g., wheelchair use, debilitating illness
Known hyperlipidemias—e.g., family history of hypercholesterolemia
Symptomatic gallstones
Migraine headaches or a past history of migraine with aura at any age
Category 4: Unacceptable health risk and should not be used
Obesity—BMI ≥40 kg/m2
Migraine headaches—with aura at any age
Known thrombogenic mutations
Raynaud’s disease—secondary with antiphospholipid antibodies and thus a ten-
dency to thrombosis
Hypertension—blood pressure ≥160 mmHg systolic and/or ≥95 mmHg diastolic;
or vascular disease
VTE—current (on anticoagulants) or past history
Valvular and congenital heart disease—complicated by pulmonary hypertension,
atrial fibrillation, history of subacute bacterial endocarditis
Hepatocellular adenoma
Angiopathic hereditary edema 3
Finally we must not forget adolescent girls with chronic diseases, which are
nowadays increasingly frequent due to the better treatment of the underlying condi-
tions; in these cases, the choice of contraceptive must consider the adolescents’
needs and their clinical situation, determined in collaboration with their specialist,
following specific guidelines. In the presence of estrogen-dependent diseases or
increased risk of venous thromboembolism, it must be considered the possibility of
using POP.
The guidelines refer to the writing of this work are:
World Health Organization—Medical eligibility criteria for contraceptive use. Fifth

edition 2015.
World Health Organization—Medical eligibility criteria for contraceptive use.
Fourth edition 2009.
Royal College of Obstetricians and Gynecologists: Faculty of Sexual and
Reproductive Healthcare Clinical Guidance; Contraceptive Choices for Young
People Clinical Effectiveness Unit March 2010
Reproductive Healthcare Combined Hormonal Contraception Clinical
Effectiveness Unit October 2011 (Updated August 2012)
Reproductive Healthcare. United Kingdom Medical Eligibility Criteria for
Contraceptive Use (UKMEC) Update. London: FRSH; 2009.
Reproductive Healthcare Clinical Guidance; First Prescription of Combined
Oral Contraception Clinical Effectiveness Unit July 2006 (Updated January
2007)
Royal College of Obstetricians and Gynecologists: Venous Thromboembolism and
Hormonal Contraception (Green-top Guideline N° 40, July 2010).
Haute Autorité de Santé, Rapport D’élaboration: Contraception chez l’homme et
chez la femme, Avril 2013
American College of Obstetricians and Gynecologists: ACOG practice bulletin—
Clinical management guidelines for obstetrician–gynecologists number 73, June
2006
Linee Guida italiane su l’efficacia e l’uso appropriato della contraccezione
intrauterina. E. Arisi, V.Bruni, A. Di Spiezio Sardo, V. Dubini, G. Gubbini,
F. Parazzini, Dicembre 2014
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5. Arisi E., Bruni V, Cosmi B, et al. 2008, Prevenzione delle complicanze trombotiche associate
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devices. ACOG, committee opinion, n. 539 (reaffirmed 2016).
7. American Academy of Pediatrics. 2014. Contraception for adolescents, pediatrics.
8. Sidney S, Cheetham TC, Connell FA, et al. Recent combined hormonal contraceptives (CHCs)
and the risk of thromboembolism and other cardiovascular events in new users. Contraception.
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9. den Tonkelaar D1, Oddens BJ. Factors influencing women’s satisfaction with birth control
methods. Eur J Contracept Reprod Health Care. 2001;6(3):153–8.
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prospective study of age, hormone dose, and discontinuation. J Clin Endocrinol Metab.
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Ovarian Cysts in Adolescence
11
M. Chiara Lucchetti
11.1 Definition and Etiopathogenesis
The gold standard for the diagnosis of an ovarian neoplasm is the ultrasound defini-
tion provided by the IOTA (International Ovarian Tumor Analysis) criteria: It is the
part of an ovary or the total ovary that is not part of the normal ovarian physiology [1].
Functional ovarian cysts: Ovarian cyst is an ultrasonographically anechoic
space, round or oval shaped, with smooth, thin wall, acoustic posterior reinforce-
ment, in absence of solid components, sepiments, and internal flow at Color Doppler.
If these features are present in formations lesser than 3 cm in diameter, these are
considered follicles. For diameters more than 3 cm, the appropriate definition is fol-
licular cysts, that is greater expanding follicles, generally not bursted for lack of
ovulation, which is a frequent event in adolescence; for this type of cysts, regardless
the age group, incidence of malignancy is less than 1%.
During adolescence, ovarian cysts are generally due to failed follicular involution:
Lack of ovulation induces follicular overgrowth, sometimes reaching huge dimensions
and, possibly, acute symptoms due to intracystic bleeding, rupture, or torsion (of the
cysts but even of the whole ovary). For this reason, such cysts are also named “func-
tional” and only a conservative approach is required, with ultrasonographic re-evalua-
tion with time. Only when a torsion is suspected a surgical approach is mandatory.
There are also cysts with features due to a bloody content inside (hemorrhagic
cysts): They are the consequence of a bleeding inside a corpus luteum or a follicular
cyst. These cysts have the appearance of a cystic complex mass, with a net-like
distribution of internal echoes (fishing net-like, web-like, etc.) or, when resorption
is present, like a solid area with concave edges (retracting clot); at Color Doppler
they have no internal flow, but generally a circumferential flow along the cystic wall
is present (fire-ring sign); the wall thickness may be variable.
M.C. Lucchetti
Bambino Gesù Children’s Hospital, Rome, Italy

172 M.C. Lucchetti
This kind of cyst, being functional (it would be better to call them “dys-
functional”) in their nature, tend to spontaneously disappear in 6–8 weeks.
Endometriosic cysts: Besides the rarity of this pathology in adolescence (especially
if the “endometrioma” stage is considered), it has to be suspected that a complex cyst
could be an endometrioma, particularly in patients with previous mullerian obstructive
malformations and chronic dysmenorrhoea. Ultrasonographically, the appearance may
be not different from that of an hemorrhagic cyst (scattered homogeneous echoes,
groundglass-like, sometimes with a fluid level, no internal flow at Color Doppler,
without solid internal nodules or neoplastic characteristics), but at a 6–12 weeks fol-
low-up, not spontaneously disappearing, it becomes evident its real nature. If not sur-
gically removed, endometriomas require at least a yearly ultrasonographic follow-up.
Complex cysts or masses: The majority of persistent ovarian solid or complex
masses (strictly defined as neoformations or neoplasms) are mature teratomas or
dermoid cysts, which are germinal tumors. Other neoplasms can be also present in
the pediatric–adolescent age, but are relatively rare. Malignant tumors represent
1–20% of all ovarian masses in pediatric age, keeping in mind that the variability is
due to the influence, on reported series, coming from pediatric general hospital or
pediatric oncological hospital.
The ultrasonographic appearance of teratomas is characterized by the presence
of hyperechogenic solid components (focal or diffuse, also named “Rokitansky
nodule”), by thin lines or “spots” as well as hyperechogenic, by the possible pres-
ence of floating spheric structures and by the absence of internal flow at Color
Doppler. At the first glance, these formations may be undistinguishable by some
luteal/hemorrhagic formations, but at ultrasonographic follow-up the fail to resolve
give the confirm of their neoplastic nature. Mature teratomas are bilateral in 12–15%
of cases, which is an important consideration to remind during the initial evaluation
and, most of all, during follow-up.
Epithelial tumors tend to assume the appearance of voluminous cystic formations
(serous or mucinous cystadenomas), with a similar aspect to that of follicular cysts,
but with dimensions usually exceeding 10 cm.
There is no uniformity of opinions, in the Literature, about dimensions to con-
sider “at risk” for the torsion of an ovarian mass. It is well known that neoforma-
tions with a diameter between 5 and 8 cm are often present in case of ovarian
torsion, suggesting to act like a “trigger” point predisposing to torsion.
Therefore, when a mass with such dimensions is addressed to a “wait and see”
approach, it is important to be aware (and to tell the parents) that an ultrasonographic
evaluation is mandatory in case of acute abdominal and/or pelvic pain. Moreover,
dimensions greater than 8–10 cm of diameter have been recently reported to be one of
the predictable factors indicating malignancy risk, either for cystic or solid masses.
11.2 Epidemiology
The estimated prevalence for ovarian masses in the pediatric–adolescent age is 2.6
cases out of 100,000 each year. Between 2008 and 2012 in the USA only 1.3% of all
ovarian cancers have been diagnosed in patients below the age of 20, giving the idea
11 Ovarian Cysts in Adolescence 173
Table 11.1 Classification of ovarian tumors according to the WHO classification and their fre-
quency in the pediatric and adolescent population
Epithelial Serous 15–20%
Mucinous
Endometrioid
Clear cell
Transitional cell
Epithelial-stromal (adenosarcoma,
carcinosarcoma)
Nonepithelial Germ cell Dysgerminoma 60–80%
Yolk sac
Monodermal
Mixed
Teratoma
Sex cord stromal Granulosa cell 10–20%
Sertoli-Leydig
Mixed
Metastases
of how rare and difficult to study this pathology could be. In a recent review of the
Literature [2], the risk of malignancy of adnexal masses in children has been esti-
mated around 19%, with a range from 2 to 59%, being the differences due to referral
bias (specialized pediatric oncologist or not) and ages of studied population.
Epithelial carcinomas, which prognosis remains poor, account for 90% of all
ovarian cancers in adults, while in children the most frequent ovarian cancer is
nonepithelial, being epithelial in less than 20% of cases (Table 11.1), with a pre-
dominance of serous and mucinous histology [3, 4]. Most often, pediatric ovarian
cancers arise from germ cells and have a good prognosis: Mangili et al. [5] reported
results from the largest database on ovarian germ cell pathologies and stated that
there are two important contributing factors to the prognosis of germ cell tumors
(GCT): first, the majority (71%) is detected at stage I, and second they respond
well to surgery and chemotherapy, leading to a 5-year survival of 95.6% and 73.2%
in stage I and advanced stages, respectively. Because of this excellent prognosis of
GCT, overall outcome of ovarian cancer in children is excellent compared with
that in adults.
The malignancy risk has been evaluated in an epidemiologic study including
more than 1000 cases [6] in which the risk stratification has clearly showed that,
related to the frequency of onset of ovarian masses, the malignancy rate is propor-
tionally higher in the 1–8 years group; in this age group, in fact, it is extremely rare
the presence of an ovarian neoformation of functional nature and therefore the risk
to be in the presence of a neoplasia is significantly higher. This is why in this age
group the clinical approach, in case of ovarian mass, has to be more prudent.
Other studies have put in evidence that, besides patient’s age, other characteris-
tics are related to malignancy risk: clinical and hormonal features of precocious
puberty or virilization (abnormal hormonal function), dimensions >8–10 cm, pres-
ence of solid components inside the formation, higher level of one or more tumor
174 M.C. Lucchetti
markers. However, in the pediatric age it doesn’t exist yet a reliable and validated
tool able to distinguish, like in the adult population, a benign from a malignant ovar-
ian mass. In fact, while a number of such tools (risk indexes, diagnostic algorithms)
have been developed for the reproductive and menopausal age (RMI, ROMA;
OVA1, LR2 and, recently, a new algorithm involving the use of protein HE4), in the
pediatric age similar efforts have not allowed similar results, perhaps due to the
eterogeneicity of the studied populations and to the small number of ovarian malig-
nancies: with these premises, so that whatever complex diagnostic tool requires
very difficult and time-consuming validation.
Box 1: Differential Diagnoses of Ovarian Cysts

• Hydrosalpynx
• Paraovarian cyst
• Hematometra/hematocolpos
• Salpyngitis
• Pelvic abscess
• Extrauterine pregnancy
• Abdominopelvic cysts not ovarian
11.3 Diagnosis
Symptoms associated with the presence of an ovarian mass are extremely variable,
coming from the total lack of any symptom (it is frequent their occasional detection
during imaging studies for other reason) to pelvic/abdominal pain (chronic/recur-
rent or acute), until clinical signs of abnormal hormonal secretion (precocious
puberty, virilization, dysfunctional uterine bleedings, etc.). There have also been
reported rare clinical manifestations associated to the presence of mature teratomas,
very similar to paraneoplastic syndromes, such as autoimmune hemolytic anemia
and immune-mediated limbic encephalitis [7, 8].
Generally, complex masses and in particular mature cystic teratomas can become
symptomatic because of their related complications: torsion (3–16%), rupture
(1–4%), infection (1%), malignant degeneration (0.17–2%).
Since presenting signs and symptoms of ovarian masses (either benign or malig-
nant) are so heterogeneous, in recent years many authors have looked for clinical
and/or imaging features in order to exclude the risk of malignancy and to increase
the number of patients candidates to ovarian preservation (wait-and-see policy, re-
evaluation, laparoscopic surgery, reduced number of oophorectomy).
Ultrasonography: In the diagnostic approach, it remains the primary tool either
for the precocious diagnosis or the follow-up, offering the possibility to reassess
in a reasonable time masses potentially suspicious so avoiding aggressive treat-
ments. Ultrasonography has, in fact, the basic requirements of spread, ease of use,
and to repeat. Ultrasonographically, the mass is considered for its main features
that are dimensions, appearance, and content, which should help in choosing the
best therapeutic approach. When the cyst is unilocular, unilateral, with thin and
smooth wall, smaller than 8 cm and without ascitic fluid, the risk of malignancy
is very low (<1%).
US is the initial modality to confirm the presence of adnexal masses and provides
their approximate size. In some cases, it characterizes the mass, such as a dermoid
cyst, by showing calcification and fat-fluid level.
Malignancies are more often complex masses with irregular edges, not well
defined, often with necrotic central areas, sepiments, and papillary projections. When
ultrasonography, even repeated after 6–8 weeks, is not diriment, the second diagnos-
tic step is represented by Magnetic Resonance Imaging; the use of Computed
Tomography is only reserved for the staging of histologically proven malignancies.
Traditionally, masses greater than 5 cm have been used as cutoff suggestive of
malignancy, with some studies using 7.5 and 8 cm. A recent study by Papic et al. [9]
showed that 56% of benign masses were >8 cm so the cutoff value of >10 cm has
been proposed as a malignancy predictor, as well as the presence of solid compo-
nents seen on imaging. Neither of these predictors was independently 100% sensi-
tive for malignancy, as 11% of malignant masses were <10 cm and 22% of malignant
masses were cystic (complex) with no solid components.
Magnetic resonance imaging: Preoperative pelvic MRI findings might change
the surgical management of pediatric patients with adnexal masses, so it is consid-
ered a valuable addition to the conventional workup in the clinical management,
especially when an extraovarian origin of the mass is suspected or a malignancy has
to be ruled out. In a study of Marro et al. [10], MRI correctly suggested benign
nature in 24 of 28 (85.7%) benign masses while US was indeterminate in 19 of these
28 (67.8%) masses. MRI is required for better characterization of ovarian masses,
for assessing likelihood of malignancy, and for staging the tumor. It is chosen for
staging of malignancy over CT scan to reduce ionizing radiation exposure in this
young and more vulnerable population.
Tumor markers: Their diagnostic significance is controversial for the possibility
of higher plasmatic values either in malignant or in benign masses: in the Literature
the rate of benign lesions associated with markers elevated values varies from 3.4 to
20%, while no more than half of the malignant forms have a higher value of one or
more markers. It creates the risk to underestimate the possibility of malignancy, but
even that of planning a too aggressive approach toward a benign lesion.
A recent paper dealing with pediatric age [9] has evidentiated that alpha-
fetoprotein and beta-HCG are highly specific for neoplastic masses since in the ana-
lyzed series no benign mass was associated with elevated values of these markers.
But the same study has identified 17% of patients with malignancies showing the
absence of any marker elevation, coming to the conclusion that the absence of tumor
markers modifications does not allow to exclude the presence of malignancy.
On the basis of such considerations, it appears reasonable to always program an
extemporaneous histologic examination when tumor markers are elevated, in order
to offer the most appropriate surgical approach, but never to plan an aggressive
surgical approach only relying on tumor markers.
176 M.C. Lucchetti
However, their use is always considered useful during follow-up of malignan-

cies, either to evaluate the answer to therapy or to early detect recurrences.
Hormones: Hormonal samples are mandatory when an abnormal hormonal pro-
duction is suspected (precocious puberty, virilization, hyperthyroidism, etc.).
Inhibin-B, progesterone, and Anti-Mullerian Hormone (AMH) are other hormones
actually under validation as possible pre- and postoperative “markers” of reduced
ovarian reserve, coming from the mass itself and/or from its surgical treatment
(open surgery or laparoscopy).
11.4 Therapy
About 60% of ovarian masses are treated surgically. Nowadays, more than 50% of
surgeries for ovarian masses in adolescents are performed laparoscopically, and most
of the patients (71–84%) undergo cystectomy rather than oophorectomy. However, of
the small number of patients who undergo oophorectomy, the majority have benign
lesions, and this has to be considered unacceptable, although still performed.
The best practical treatment of pediatric and adolescent ovarian masses is not a
well-defined topic because of the lack of markers or validated indicators of malig-
nancy. Considering neoplastic masses, very different approaches are described and
followed, particularly for stadiation of germ cell tumors compared to epithelial and
stromal, having developed in recent years extremely conservative strategies for the
first ones (such as laparoscopy, ovary-sparing surgery, tumorectomy with preserva-
tion of residual ovarian tissue) and more aggressive for the others. In recent years,
preservation rates in girls with benign ovarian masses have increased from 15% in
1999 to 39–61%, but as stated by Papic et al. [9] it is likely less than it could be.
Besides, it is always dutiful to consider that for many ovarian neoplasms the
surgical treatment is needed as an emergency procedure because of a secondary tor-
sion or rupture.
The main target in the management of an ovarian mass in pediatric and adoles-
cent age should be to preserve the ovary, without betraying the oncological princi-
ples, most of all as far as it regards the stadiation, considering that during surgery
the histology is not known until pathologic exam is performed.
The general basic rules in the management of ovarian masses in this age group
should therefore be the following:
1 . To establish cyst/mass main features

2. To avoid any surgery for functional cysts
3. To exclude the presence of neoplasms
Laparoscopic surgery is considered the gold standard in the treatment of benign

ovarian masses. There are still existing controversies regarding malignancies, and
for this reason a lot of “suspected” masses are still treated with laparotomies by
gynecologists and pediatric surgeons. While there is general agreement about the
use of laparoscopy when a malignancy is reasonably excluded during preoperative
Table 11.2 2014 FIGO ovarian cancer staging

Stage I. Tumor confined to ovaries or fallopian tube(s)
IA: Tumor limited to one ovary (capsule intact) or fallopian tube; no tumor on ovarian or
fallopian tube surface; no malignant cells in the ascites or peritoneal washings
IB: Tumor limited to both ovaries (capsules intact) or fallopian tubes; no tumor on ovarian or
fallopian tube surface; no malignant cells in the ascites or peritoneal washings
IC: Tumor limited to one or both ovaries or fallopian tubes, with any of the following:
IC1: Surgical spill
IC2: Capsule ruptured before surgery or tumor on ovarian or fallopian tube surface
IC3: Malignant cells in the ascites or peritoneal washings
Stage II. Tumor involves one or both ovaries or fallopian tubes with pelvic extension (below
pelvic brim) or primary peritoneal cancer
IIA: Extension and/or implants on uterus and/or fallopian tubes and/or ovaries
IIB: Extension to other pelvic intraperitoneal tissues
Stage III. Tumor involves one or both ovaries or fallopian tubes, or primary peritoneal cancer,
with cytologically or histologically confirmed spread to the peritoneum outside the pelvis and/
or metastasis to the retroperitoneal lymph nodes
IIIA1: Positive retroperitoneal lymph nodes only (cytologically or histologically proven):
IIIA1 (i) Metastasis up to 10 mm in greatest dimension
IIIA1 (ii) Metastasis more than 10 mm in greatest dimension
IIIA2: Microscopic extrapelvic (above the pelvic brim) peritoneal involvement with or without
positive retroperitoneal lymph nodes
IIIB: Macroscopic peritoneal metastasis beyond the pelvis up to 2 cm in greatest dimension,
with or without metastasis to the retroperitoneal lymph nodes
IIIC: Macroscopic peritoneal metastasis beyond the pelvis more than 2 cm in greatest
dimension, with or without metastasis to the retroperitoneal lymph nodes (includes extension of
tumor to capsule of liver and spleen without parenchymal involvement of either organ)
Stage IV. Distant metastasis excluding peritoneal metastases
Stage IVA: Pleural effusion with positive cytology
Stage IVB: Parenchymal metastases and metastases to extra-abdominal organs (including
inguinal lymph nodes and lymph nodes outside of the abdominal cavity)
evaluation, there are not precise rules to achieve this “reasonably exclusion,”
although some authors have published data aimed to this.
There are two main stadiation systems for ovarian pediatric masses: one from the
International Federation of Gynecology and Obstetrics (FIGO) and one from the
Children’s Oncology Group (COG), regarding only germ cell tumors (Tables 11.2
and 11.3). The Children’s Oncology Group (COG) established also the current con-
sensus guidelines for appropriate staging procedures among pediatric patients with
ovarian germ cell tumors [11] (Table 11.4).
Regarding cystic mature teratomas, the Literature based on adult age suggests
that laparoscopic excision is a safe procedure, without an increase in the number of
recurrences when compared with laparotomy [12]. The decision to use the same
approach for the pediatric age has been more cautious, and it is still considered as
depending on the laparoscopic experience of the single surgeon and on the patient’s
age. The standard treatment of a cystic mature teratoma is still reported as ovariec-
tomy by “open” surgery, but recently many authors have proposed the excision of
the lesion (open or laparoscopically) without considering oophorectomy.
178 M.C. Lucchetti
Table 11.3 Staging system for pediatric ovarian germ cell tumors (COG)
Stage I
Limited to ovary (ovaries); peritoneal washings negative; tumor markers normal after
appropriate half-life decline (AFP 5 days, HCG 16 h)
Stage II
Microscopic residual or positive lymph nodes (2 cm)
Peritoneal washing negative for malignant cells, tumor markers positive or negative
Stage III
Lymph node involvement (2 cm) gross residual or biopsy only; contiguous visceral involvement
(omentum, intestine, bladder); peritoneal washings positive for malignant cells; tumor markers
positive or negative
Stage IV
Distant metastases, including liver
Table 11.4 2004 COG guidelines for GCT staging

– Collection of ascites or peritoneal washings
– Examination of peritoneum and biopsy of any abnormality encountered
– Gross examination of retroperitoneal lymph nodes by visual inspection and direct palpation
with subsequent biopsy of abnormalities encountered
– Examination of the omentum with removal of abnormalities encountered
– Gross examination of the contralateral ovary with biopsy of abnormalities encountered
– Complete resection of ipsilateral ovary without tumor spill or capsule violation
In 2014, the Gynecologic Cancer Intergroup (GCIG) formulated a consensus on

ovarian germ cell tumors [13]; since most tumors are unilateral and diagnosed as stage
I disease, fertility-sparing surgery appears to be safe. In case of FIGO stage II disease
or higher, surgery has to be extended, keeping in mind that the uterus usually can be
preserved even in case of a bilateral tumor. The administration of neoadjuvant chemo-
therapy, prior to debulking surgery (as is accepted in widespread epithelial ovarian
cancer in adults), can be considered in children with widespread dysgerminomas since
the tumor is highly chemosensitive. Standard chemotherapy for advanced or incom-
pletely resected GCT is based on bleomycin, etoposide, and cisplatinum; in carboplati-
num replacing cisplatinum is also suggested, or even with ifosfamide replacing
bleomycin. It is expected that more than 90% of children will survive their disease.
The majority of epithelial ovarian cancers in children reported in the Literature
are mucinous ovarian cancers or low-grade serous ovarian cancers. Both for chil-
dren and for adults, serous ovarian cancer will present most often at stage III or IV,
with the typical features of a bloated abdomen, dyspnea, and abdominal pain.
Epithelial ovarian cancer in children is not restricted to serous and mucinous carci-
noma; there have been described cases of clear cell ovarian carcinomas, Brenner
tumor, endometrioid ovarian carcinomas, small cell ovarian cancers of the hyper-
calcemic type, sarcomas. In contrast to the balanced and well-reported treatment
schedule for children with GCTs, epithelial ovarian cancer in children is treated as
adults with a combination of surgery and platin-based chemotherapy. Fertility spar-
ing surgery is not an option, because it is very important that all macroscopic tumor
is resected, particularly for stages II–IV.
The mainstream surgical treatment (open surgery or laparotomic surgery) is now

considered appropriate only when there is the suspicion of a neoplastic, malignant
mass. In this case, the open surgery allows that oncological stadiation is performed
easier and correctly (evaluation of limphnodes, mesenter, peritoneum, ascitic fluid
aspiration for citology), that the radical resection of the mass is verified, and that
contralateral ovary is properly palpated (little internal neoformations may result
hardly palpable, so not recognizable at all at laparoscopy). Traditional surgery is
also associated with lesser incidence of ruptures or “spillages.” On the other hand,
surgical operation results, in the majority of cases, much more aggressive than
needed, mostly considering the small number of malignancies in this age group.
An open approach is commonly used when malignancy is suspected, and it has
also been recommended for large cysts owing to better visualization which may
lead to decreased tumor rupture and improved ovarian preservation. However, in a
study by Papic et al. [9] laparoscopy demonstrated to be an effective approach for
ovarian preservation even with large benign masses. Additionally, there was no
increase in tumor spillage rates between laparoscopic and open groups, and the
length of stay was shorter in the laparoscopic group. The overall ovarian preserva-
tion rate for benign masses in that study was 24%, which is lower than other recent
series reported (39–61%).
The complete ovarian resection (oophorectomy or salpingo-oophorectomy) is
indicated on the basis of the tumor extension. In germ cell tumors not macroscopi-
cally involving the Fallopian tube, the tube of the affected side can be preserved
without risk. Stage IA tumors (serous borderline, stromal sexual cords and germ cel
tumors) also have been demonstrated to be safely treated with cystectomy/tumorec-
tomy and strict follow-up. It is also possible to plan a possible second surgical
procedure aimed to stadiate a patient initially treated with cystectomy alone, but this
option has to be formulated on individual basis, considering the type on neoplasms,
the pathologic stage, the grade, the risk that a chemotherapy will be needed and the
compliance. It has to be discouraged, indeed, the routine biopsy of the contralateral
ovary to avoid a further damage to future fertility.
Recurrences and mortality have been reported with variable values in different
series: from 4% for both [11] to 16% for recurrences and 11% for mortality [14] to
0% for both [15, 16].
For stage I germ cell tumors surgical resection alone seems to be the best
approach in order to accomplish the oncologic management and the fertility preser-
vation. For more advanced stages, chemotherapy with bleomycin, etoposide, and
cisplatinum gives generally optimal results; after three to four chemotherapy cycles,
a second-look surgery is required to document the local answer and to eventually
remove residuals of disease. Survival is good even in such cases (more than 90%
after 5 years).
Even for stromal sexual cords in stage IA and low histologic grade, surgical
treatment alone is proposed. Chemotherapy is reserved for more advanced stages,
higher histologic grade or evidence of tumor rupture during surgery. Survival is
good for stage I lesions (more than 90%), while for higher stages and grades sur-
vival after 5 years can be lower than 60%.
180 M.C. Lucchetti
Malignant epithelial tumors are generally unusual before menarche and are
mainly represented by serous borderline tumors with low malignancy potential and
very good prognosis (89% survival at 20 years); the evolution to adenocarcinoma
has only seldom been described. Proposed treatment is monolateral salpingo-
oophorectomy and subsequent strict follow-up. For the very rare cases of adenocar-
cinoma, surgery has to be radical with rigorous adherence to FIGO guidelines.
When a cyst (of unknown origin) is associated with ovarian torsion, suggested
treatment is always derotation and cystectomy (either in traditional surgery or lapa-
roscopically); when the ischemic state of the ovary is severe (black-bluish ovary) or
there is the suspicion of a solid mass inside the enlarged ovary, it seems appropriate
to schedule a “second-look” surgery, avoiding unnecessary oophorectomies. The
need for oophoropexy is a very discussed topic, either for the torsed ovary or for the
contralateral one.
Cass et al. [15] and Bristow et al. [17] reported an 85% and 100% of ovarian
masses with torsion treated with oophorectomy, respectively. Irreversible ischemic
damage to the ovary and the concern for malignancy have been attributed to the high
rates of oophorectomy in these masses. With increasing evidence of complete ovar-
ian recovery after detorsion and low rate of malignancy (only 2% of ovarian masses
with torsion were malignant in the study of Papic et al. [9]), current recommenda-
tion includes detorsion and cystectomy, without complete oophorectomy, followed
by postoperative surveillance, regardless of how ischemic or necrotic the ovary
appears intra-operative.
In the treatment of ovarian masses (either cystic or solid) is not indicated any
hormonal therapy. It has been well demonstrated, in fact, that estroprogestinic ther-
apy has no effect in the resolution of cystic masses (when their nature is functional,
they are spontaneously disappearing) nor in time of resolution, as recently shown in
a Cochrane’s review by Grimes et al. [18].
Finally, aspiration of ovarian cysts has no indication and is considered obsolete
because of its very low specificity (32%); if masses are complex there is the risk to
spread teratomas and to induce a chemical peritonitis. If masses are cystic, unilocu-
lar, simple, according to their dimensions, the only treatment option is observation
or excision (laparoscopic or open surgery) [19].
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and measurements to describe the sonographic features of adnexal tumors: a consensus opinion
from the International Ovarian Tumor Analysis (IOTA) group. Ultrasound Obstet Gynecol.
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Female Genital Mutilations
12
Lucrezia Catania, Omar Abdulcadir,
and Jasmine Abdulcadir
Abbreviations
AOU Azienda Ospedaliera Universitaria

DAIMI Dipartimento Materno infantile
FGM/C Female Genital Mutilation/Cutting
WHO World Health Organization
12.1 Introduction
WHO defines Female Genital Mutilation (FGM) as all procedures that involve the
partial or total removal of external genitalia or other injury to the female genital
organs for non-medical reasons [1]. The practice is still being reported in 30 coun-
tries in Africa and in some countries in Asia and the Middle East (Yemen, Iraqi,
Kurdistan, Indonesia and Malaysia; there is a high prevalence of FGM in some
specific geographical areas) [1, 2]. Some forms of FGM have also been reported in
specific ethnic groups in Central and South America [1].
In the last decades, because of international migration, the number of affected or
at risk of FGM girls and women has increased in high-income countries [3, 4].
L. Catania, M.D. (*) • O. Abdulcadir, M.D.

Regional Referral Centre for the Treatment and Prevention of FGM, Health Promotion of
Immigrant Woman, DAIMI, AOU-Careggi Florence, Florence, Italy
J. Abdulcadir, M.D.
Department of Obstetrics and Gynecology, Geneva University Hospitals, Geneva,
Switzerland

184 L. Catania et al.
Unicef has estimated that over 200 million girls and women worldwide live with
some forms of FGM and the negative health consequences [2]. Every year almost
three million girls and women are at risk of FGM [4].
Healthcare providers in all countries may face the need to provide healthcare to
this population. Unfortunately, health workers often do not know the different types
of genital mutilations; they are unaware of the real health consequences and are inad-
equately trained in diagnosing and treating these properly. The opportunities to iden-
tify FGM are frequently missed [5]. Paediatricians/gynaecologists have to be able to
identify children/girls who have had some forms of FGM to offer appropriate care,
treatments and information and to protect girls at risk. Better-trained personnel will
lead to improved communication, higher rate of accurate diagnosis and better health
care offer. This could also have an impact on prevention of the practice for future
generations [5]. An appropriate training can also avoid stigmatization and misdiag-
nosis, with possible serious legal, social and psychological consequences for families
that may be unjustly persecuted after the incorrect reporting to the court [6].
12.2 Classification and Description
According to the World Health Organization (WHO), female genital mutilation is

classified into four types and subdivided into subtypes (Table 12.1).
An agreed-upon classification and a corresponding correct morphology for each
type of female genital mutilation are important for clinical practice, management,
recording and reporting, as well as for research on prevalence, trends and
consequences of female genital mutilation. A visual reference and learning tool for
Table 12.1 World Health Organization classification of female genital mutilation

Type I: Partial or total removal of the clitorisa and/or the prepuce (clitoridectomy)
Type Ia: Removal of the clitoral hood or prepuce only
Type Ib: Removal of the clitorisa with the prepuce
Type II: Partial or total removal of the clitorisa and the labia minora, with or without excision of
the labia majora (excision)
Type IIa: Removal of the labia minora only
Type IIb: Partial or total removal of the clitorisa and the labia minora
Type IIc: Partial or total removal of the clitoris,a the labia minora and the labia majora
Type III: Narrowing of the vaginal orifice with creation of a covering seal by cutting and
apposition of the labia minora and/or the labia majora, with or without excision of the clitoris
(infibulation)
Type IIIa: Removal and apposition of the labia minora
Type IIIb: Removal and apposition of the labia majora
Type IV: Unclassified All other harmful procedures to the female genitalia for non-medical
purposes, for example, pricking, piercing, incising, scraping and cauterization
Reprinted from [1]
a
In the World Health Organization classification, when there is reference to removal of the clitoris,
only the glans or the glans with part of the body of the clitoris is removed. The body or part of the
body and the crura of the clitoris remain intact as well as the bulbs, two other sexual erectile struc-
tures [7]. This anatomic notion is very important in education and in treatment of sexual
dysfunction
12 Female Genital Mutilations 185
healthcare professionals is now available. This tool can be consulted by caregivers

when unsure on the type of FGM diagnosed, used for training and surveys for moni-
toring the prevalence of female genital mutilation types and subtypes and be used in
legal disputes Figs.12.1, 12.2, and 12.3 [8].
Fig. 12.1 Female genital mutilation type Ia: removal of the prepuce of the clitoris or clitoral hood
(female circumcision). Courtesy of Jasmine Abdulcadir
Fig. 12.2 Female genital mutilation type IIc: partial or total removal of the clitoris, the labia
minora and the labia majora. Courtesy of Jasmine Abdulcadir
Fig. 12.3 Female genital mutilation type IIIb without cutting of the clitoris before and after defib-
ulation. Courtesy of Jasmine Abdulcadir
12.3 FGM, Religion and Social Factors
FGM is not prescribed by any religion even if it is often thought that they are a
religious obligation. Women and children with FGM/C can have Islamic, Christian,
Jewish or Animist religion depending on their ethnicity.
Factors used to justify and perpetuate FGM are multiple and diverse: social and
peer acceptance, preparation for adulthood and marriage, removal of dirty, mascu-
line and impure parts of the genitalia, reduce sexual impulses to ensure chastity and
overall maintain cultural identity [9].
The young girls who come from these cultures have to go through this painful
experience, painful both physically and psychologically, to become part of the
female group, and to be worthy of becoming wives and mothers 1 day.
While FGM leaves the ability for procreation intact, FGM mutilates the female
body in the most intimate and sensitive parts which have the only function, so far
discovered, of giving sexual pleasure. Furthermore, in the majority of cases, the sub-
jects who are subjected to FGM are not in a position to oppose. This practice is rec-
ognized as an abuse and violence against minors and a violation of human rights [1].
FGM is practiced at different ages depending on the country of origin. It may be
performed from few days after birth to 15 years, usually before the first period [2].
Among certain ethnic groups, it can be performed after the marriage or after giving
birth. Most of girls examined for a study on FGM in a London safeguarding clinic
were less than 10 years old when FGM was performed [10].
12.4 Complications
FGM can be responsible for heath complications, the severity of which depends on
different factors such as quantity of removed tissue (types and subtypes of FGM),
pre-existing health and nutritional condition of female baby/child, childhood feel-
ings and emotions (often fear coexists with pride), hygienic and sanitary modalities
and instruments used for the practice (unhealthy or sanitary tools, traditional practi-
tioner or physician or nurse, etc.).
Although FGM is carried out during childhood, the available medical literature,
often coming from countries of the diaspora, has mainly focused on the obstetric
and gynaecological impact on adults. However, FGM is illegal and in many coun-
tries it is mandatory for health professionals to report to the police when a case of
mutilation has been disclosed or when physical signs or symptoms of FGM are seen
in a minor [9, 10].
FGM can be responsible for short- and long-term health complications [1].
The short-term effects of FGM afflict children/girls immediately after the procedure.
Haemorrhage, infection of the wound, pain, and shock are reported as common.
Anaemia has been reported in 38% of girls after FGM [11]. Because of the use of
unsterile tools, cases of tetanus, transmission of blood-borne infections such as
Hepatitis B and C and HIV have been described. The real number of children who
died for the operation is not officially registered [12].
Long-term complications may afflict women with FGM for long life. Their care and
treatment require specific medical attention and sensitivity as women can be unaware
that their symptoms are caused by FGM or that they underwent the practice. The most
frequent complications are well described in the medical literature. Some others of
them are frequent and unknown. The most serious complications concern FGM type II
and III, which has also been more investigated compared with type I and IV.
Recurrent vaginal-urinary tract infections and dysuria (including prolonged mictu-
rition, drop by drop urinary stream flow through the tiny orifice of the infibulation)
have been reported in up to 22% of women following FGM [9, 13]. When in the scar
of FGM type III there are several orifices, urination is rainy. With the stagnation of the
urine behind the infibulation scar, small stones can be hidden behind it. A prolonged
bladder outlet obstruction caused by the infibulation (urethral meatus is covered by
the scar) can cause myogenic, morphological and neurogenic changes which lead to
detrusor overactivity, urinary urgency, with incontinence, frequency and nocturia [14].
Cysts in the scar are frequent and sometimes may evolve in abscesses or grow
very much [15].
Post-traumatic clitoral neuroma (benign tumour arising after a section or injury
to a nerve caused by the regenerative disorganized proliferation of the lesioned
nerves) can be a consequence of FGM. Sometimes neurinomas are asymptomatic or
they cause chronic pain or severe pain during sexual activity. In that case, the
treatment seems to be surgical excision. Considering the high frequency of clitoral

cysts in case of infibulation, clitoral neuroma should be considered in the differen-
tial diagnosis when a cyst is painful [16].
Haematocolpos/haematometra has to be suspected in girls coming from coun-
tries with tradition of FGM when the absence of the menarche coexists with devel-
oped secondary sexual characteristics. The excessive tightness of the vaginal introits
caused by an infibulation could be the cause. In that case, a defibulation can solve
such complication.
Mental health problems such as anxiety, post-traumatic stress disorder and
depression have been linked to FGM [17, 18].
The first sexual intercourses can be painful and sometimes remain so for life if
not treated appropriately. In women with FGM type III, penetration is difficult or
even impossible and a defibulation should be offered. When there is a sexological
problem, it should not be assumed that the mutilation is the only cause responsible
for it. Other factors may cause a sexual dysfunction, including other past traumatic
events, and it is necessary to provide sexual education, information and proper treat-
ment, involving the partner if necessary.
It is important to support adolescents with FGM because the social stigmatiza-
tion and the negative messages from the media regarding FGM may provoke nega-
tive expectations on the possibility of experiencing sexual pleasure creating sexual
dysfunction. They should have correct information on anatomy, sexual functioning,
and appropriate treatment [1, 19, 20].
Negative impact on obstetric outcomes for the mother and baby has been
described (increased risks of post-partum haemorrhage, C-section, perineal trauma
and perinatal death) [1, 9, 21]. Risks were increased with more extensive FGM.
WHO (2016) has published the guidelines on the management of health compli-
cations from female genital mutilation to provide up-to-date, evidence-informed
recommendations on the management of health complications from FGM and to
provide standards that may serve as the basis for developing local and national
guidelines and healthcare provider training programmes [1].
12.5 Defibulation and Clitoral Reconstruction
Defibulation is a surgical procedure for reversing infibulation and opening the vagi-
nal introitus, uncovering the urinary meatus and, when not excised, the clitoris. The
operation improves the urinary and menstrual flow, reduces the dysmenorrhea and
dyspareunia, solves the urinary and vaginal infections, and facilitates instrumental
examination and the spontaneous delivery. It can be partial (opening of the scar up
to the urethral meatus) or total (opening up to the clitoris). Defibulation is the most
important treatment of the infibulation. It is recommended to give appropriate brief-
ing and psychological support before and after the operation [1].
Clitoral reconstruction is a relatively new surgical technique which implies the
resection of the scar covering the clitoral stump, sectioning the suspensory ligament,
removing the fibrosis surrounding the mobilized stump, and repositioning it as a neo-
glans. Even if recent reports claim that surgical clitoral reconstruction may restore
sexual function and reduce pain [22], available studies of this technique are flawed
with lack of long-term follow-up and psychosexual assessment [1, 23, 24]. In absence
of conclusive evidence on its safety and efficacy, at present it is not recommended by
the available guidelines. When performed, post-op management should be multidisci-
plinary and guarantee adequate analgesia. Some authors reported that genital pain
after clitoral reconstruction can recall memories of the genital mutilation [25].
12.6 Clinical Management of FGM
In high-income countries, it is not usual to see children who have acute symptoms
due to a recent mutilation of the genitals. There is also a trend towards less invasive
types of FGM with less tissue damage and lower acute health pathologies. A pricking
or a small incision of the prepuce (Type IV FGM) or a little excision of the prepuce
(Type Ia) is difficult to be diagnosed once healed, as there is no or a very small scar.
Creighton states that while gynaecological operators are not familiar with the range
of normal genitals in children, paediatricians have more experience but they usually
tend to concentrate on the hymenal and anal findings and often do not examine the
clitoris in detail unless specifically looking for FGM [9]. Paediatricians may also be
unfamiliar with the different types of FGM particularly where physical signs are
minimal or absent [9, 26, 27]. The examiner should be trained on these subjects and
in the use of the colposcope. Detection of type IV FGM might be easier and docu-
mentation for peer review or to seek a second opinion from an expert would be pos-
sible. In addition, photo documentation for all Types of FGM will be required in the
case of any subsequent legal proceedings. In presence of a child with FGM just
arrived from the original country (because of migration or adoption), general assess-
ment of the complications should be made. If she is infibulated, a deinfibulation to
open the vaginal scar tissue can be offered. Girls who are asymptomatic may defer
the operation until adulthood and should be given contact to access the appropriate
service prior to sexual activity or marriage. Defibulation procedures are usually per-
formed under local anaesthetic in adult women but in children a brief general anaes-
thetic would be more appropriate. Evidence is lacking but the psychological impact
of a surgery performed on the site of the ancient trauma may be severe with flash-
backs and memories. Input from a child psychologist with experience in working
with children with FGM and their families should be available [10, 27, 28]. When a
child is confirmed to have FGM, it is a professional requirement to report it and it is
important to safe other younger sisters or other young female relatives. Parents
should be made aware of the law against FGM [27].
Conclusion
The health needs of children with FGM are different from those of adults for
whom there are official guidelines for a correct management of the physical and
mental consequences. Skills needed for diagnoses and treatment of FGM in chil-
dren should be specific. Paediatricians need to be familiar with the health impli-
cations and physical findings in children with FGM. They must also be aware of
the legal status of FGM and their own responsibilities with regard to recording
and reporting FGM. Paediatricians working within safeguarding clinics are

likely to be increasingly called upon to assess whether or not a child has had
FGM. Confirmation of FGM in young children may be difficult. Genital findings
may be subtle and this may be due to the performance of less invasive types of
FGM in girls at a younger age.
In conclusion, when receiving children from communities with tradition of
FGM it is important to confirm or not a FGM and its eventual complications;
offer appropriate treatment or referral; assess the real risk of FGM in a child and
her relatives who did not undergo genital mutilation; inform and communicate
with them and their parents belonging to different cultures, avoiding stigmatiza-
tion. In case of language barriers, family members or friends should never trans-
late. Certified interpreters should be used. It is also useful to be familiar with
safeguarding procedures, multiagency working and the legal implications [27].
References
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tion. Maggio Office of the United Nations High Commissioner for Human Rights (OHCHR),
Joint United Nations Programme on AIDS (UNAIDS), United Nations Development
Programme (UNDP), United Nations Economic Commission for Africa (UNECA), United
Nations Educational, Scientific and Cultural Organization (UNESCO), United Nations
Population Fund (UNFPA), United Nations High Commissioner for Refugees (UNHCR),
United Nations Children’s Fund (UNICEF), United Nations Development Fund for Women
(UNIFEM), World Health Organization (WHO). Eliminating female genital mutilation: an
interagency statement. Geneva: World Health Organization; 2008. http://apps.who.int/iris/bit-
stream/10665/43839/1/9789241596442_eng.pdf. Accessed 26 April 2016.
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unicef.org/resources/female-genital-mutilation-cutting-a-global-concern.html. Accessed 26
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doi:10.1016/j.ijgo.2013.11.016.
6. Detenidos y separados de sus hijas por una ablación genital inexistente Cataluña revisará el
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com/ccaa/2017/01/28/catalunya/1485616989_147479.html.
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Sexual anatomy and function in women with and without genital mutilation: a cross sectional
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cal estimates of the numbers of affected women living in England and Wales and girls at risk
2014. Equality Now and City University London. http://www.equalitynow.org.
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lation. Int J Gynaecol Obstet. 2013;123:21–3.
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type III. BMJ Case Rep. 2013;2013. pii: bcr2012008155. doi: 10.1136/bcr-2012-008155.
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doi:10.1111/j.1743-6109.2011.02558.x.
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Sexual Abuse and Genital Trauma
13
Maria Rosa Giolito, Giulia Mortara, and Monica D’Amato
13.1 Definition
“Sexual abuse occurs when a child is engaged in sexual activities that the child cannot
comprehend, for which the child is developmentally unprepared and cannot give consent,
and/or that violate the law or social taboos of society. The sexual activities may include all
forms of oral-genital, genital, or anal contact by or to the child, or non-touching abuses,
such as exhibitionism, voyeurism, or using the child in the production of pornography.
Sexual abuse includes a spectrum of activities ranging from rape to physically less intrusive
sexual abuse” [1].
13.2 Introduction and Epidemiology
Child sexual abuse is a social and public health problem, with potentially devastat-
ing and expensive consequences. Latest studies report that over one billion children
from 2 to 7-years-old experienced violence; worldwide, the World Health
Organization estimate that every year 1,500,000 people lose their life due to vio-
lence [2–4].
Child abuse outcomes can be both physical and/or psychological reflecting on
social costs. Each abuse can leave indelible signs willing to persist, signs that if not
M.R. Giolito (*)

Dipartimento Materno Infantile ASL Città di Torino, Turin, Italy
G. Mortara
S.C. Consultori Familiari e Pediatrici ASL Città di Torino, Turin, Italy
M. D’Amato
S.C. Legal Medicine, A.O.U. “Città della Salute e della Scienza”, Turin, Italy

194 M.R. Giolito et al.
properly detected and treated can determine permanent physical and psychological
damages [5–8].
The mechanism that tries to explain how childhood negative events influence in
a significant way people’s health and welfare it’s well represented by the Adverse
Childhood Experiences (ACEs) Pyramid (Fig. 13.1) [9].
Among the many possible symptoms we mention: growth disorder, cognitive
disorder, sleep and food-related disorder, psychosomatic disorder, anxiety and
depression, alcohol and substance abuse, smoking, post-traumatic stress disorder,
psychiatric disorder, self-injuring behaviors, suicide, cardiovascular pathologies,
and cancer [10–12].
Not less important is the trans-generational transmission: from a 2005 study has
been found especially in poly-victimization cases, abused children tend to become
abusers in adulthood [13].
The most suitable approach consists of four fundamental steps:
• Investigate and identify problem extension

• Highlight causes and risk factors
• Actuate treatment programs
• Identify prevention programs [4, 14–17]
It’s extremely important to identify the phenomena extension, in order to define

and apply customized and efficient strategies to face the problem. Face means being
Death
Early Death
Disease, Disability
and social problems
Adoption of
Health-risk Behaviors
Social, Emotional, &

Cognitive Impairment
Adverse Childhood Experiences

Birth
Fig. 13.1 The impact of adverse childhood experiences on the lifespan

13 Sexual Abuse and Genital Trauma 195
able to detect, have the medical competences to assist the victim, and provide the
most adequate treatments, but also implement prevention strategies [18].
The exact child abuse prevalence is unknown. This is due to several factors:
absence of unified and shared protocols, victim’s difficulties in disclosing due to the
own nature and dynamics of the sexual abuse, low conviction rate in judiciary paths
[19, 20].
Many times sexual abuse histories are revealed in adulthood. The NSPCC
(National Society for the Prevention of Cruelty to Children) performed many stud-
ies, and from one of them, conducted on 2869 adults from 18 to 24-years-old, and
the 11% of them reported to have been abused in childhood. Furthermore, comes
out that 16.5% of the people from 11 to 17-years-old and the 24.1% of the people
from 18 to 24-years-old, experienced sexual acts during childhood [21].
It’s important, for the detection, to know the risk factors, in particular the envi-
ronment around the child and his relationships. A recent research on child abuse in
Malaysia shows that a low socioeconomic status, dis-harmonies or familiar con-
flicts, and substance abuse of parents psych disorders can be related to an increase
in sexual abuse risk for little girls [22, 23].
Prevention programs have been applied by several world organizations (WHO,
UNICEF) involving health, social, educational and justice services, summarized
with the acronyms THRIVES (Training in parenting—Household economic
strengthening—Reduced violence through legislative protection—Improved ser-
vices—Values and norms that protect children—Education and life skills—
Surveillance and evaluation) that have the potential to reach and sustain the efforts
to prevent violence against children [2, 3].
13.3 Medical Examination
Victims usually can’t give a name to what had happened to them and they can’t
explain the feelings in words, but their body can tell their stories even if children
can’t. Victims do not always receive the type of help they really need and each and
every therapy is going to be relatively inefficient if the underlying traumatic experi-
ence is not detected and faced.
The medical examination usefulness is undisputed for the identification of the
clinical situation and/or the various injuries of nature and a treatment program launch.
It’s vital to detect the sexual abuse as soon as possible to prevent consequences.
At this point, clinicians have a key role in the identification, management and report
of suspected sexual abuse, and many health organizations promote training pro-
grams for clinicians in order to support sexual abuse detection and improve the
victim taken in charge.
Clinicians must be able to identify abuse signs and symptoms, diagnose, and
provide medical treatments in case of injuries, infections, or other pathological con-
ditions related or not related to the abuse. It’s important that they perform a com-
plete and accurate medical evaluation, examining the little girl from the head to the
toes, reassuring her when it’s possible, on her health status [24–26].
The minor victim of sexual abuse can in fact perceive her own body as “dam-
aged,” thus the psychological reassurance related to her body’s status and her integ-
rity represents a fundamental moment along the recovery path in order to avoid the
victim to keep saying “I still feel like I am not normal” [27, 28].
During the medical examination, the clinician has to accurately collect the docu-
mentation, also photographs, that could be helpful in court site, where he could be
asked to give testimony [29].
The testimony in court needs competences that are not always obtained in clinical
practice. Guidelines are available in literature and essential indications for a correct
and adequate testimony for the doctors that are usually asked to explain why the phys-
ical examination alone does not prove or disprove that sexual abuse occurred [30, 31].
It is the clinicians’ duty to report to the court the child prejudice status according to
the state legislation and he must activate, if needed, protection measures to avoid further
abuses, also, if necessary, with hospitalization or urgent admission foster care homes.
Even though the importance of specific timing is widely documented in literature,
often clinicians don’t have adequate knowledge and technical and emotional skills to
deal with a suspected sexually abused girl. Therefore, to limit diagnostic errors (false
positive/false negative) and further traumas for the child, it’s important that medical
examination is performed by professionals with specific skills [21, 30, 32, 33].
13.4 Reception
It is not always possible to schedule the first medical examination for a little girl
suspected of sexual abuse, thus usually the first examination can’t be performed in
the best context.
It is fundamental to try to ensure a quiet and discreet environment, not to trauma-
tize the little girl further, ensuring a second clinician’s presence to support both the
clinician and the child.
It is important to perform the examination at the presence of a trusted adult—
unless the girl prefers he/she doesn’t stay—who remains with her during the clinical
evaluation and assists her while she gets undressed and dressed. It is fundamental to
have time to be able to obtain the girl’s trust and agreement, providing explanations
on examination modalities and reasons, and using a proper language suitable for her
age. It is important to ensure privacy, not to use strength or deceits during the exam.
In particular, it’s recommend to reschedule the visit if the child is not calm while
examining the genital area and she doesn’t cooperate [25, 34–36].
It is also recommended not to touch the genital area and breast, unless if needed
for the clinical evaluation: in this case, the little girl must be informed and her agree-
ment obtained. It is important to observe and report the behavior and the emotional
state during the examination [37].
Sedation is performed very rarely, when the benefits are doubtfully higher than
potential risks, for example, in case of vaginal and/or anal injuries that need surgical
treatment, in case of foreign vaginal and/or ano-rectal bodies, and in case of impor-
tant bleeding or of nature to be diagnosed.
13.5 Medical History
The medical history data collection and the reported child story are the base for the
medical evaluation.
It is important that professionals are competent, empathic, not judging and objec-
tive. Often the sexual abuse diagnosis is exclusively based on the medical history so
the data collection accuracy is fundamental. Inductive questions should never be
asked; instead, the spontaneous story should be reported paying attention to tran-
scribe the girl’s sentences integrally and to avoid making her repeat the story many
times. Congruence check is necessary between the dynamic facts, timing and
observed clinical status, scheduling possible further investigations (blood exams,
pharynx/vaginal/rectal swabs, instrumental exams) [27].
13.6 Objective Examination
During the medical examination, the little girl must be examined “from the head to
the toes” analyzing each single part of her body and paying attention to cover the
different areas as the examination proceeds. During the objective examination, the
genital area evaluation has to be done. It’s good practice to examine also the oro-
pharynx because oro-genital contacts are recurring in sexual abuse. It is fundamen-
tal to report any careless signs, paying special attention to the body, hair, and oral
hygiene. Weight and height have to be measured as well as the pubertal stage
according to Tanner’s stages. It is important to perform a complete evaluation giving
back to the little girl, if possible, the “body integrity” concept that could be pre-
cluded if the examination is limited to the anal-genital area only [38–41].
13.7 Ano-genital Area Examination
To examine the ano-genital area, the three positions shown in the figure are used
(Fig. 13.2):
In Figure 13.2 the supine position, usually well accepted, gives a good visualiza-
tion of the vulvar area, the vaginal orifice (a). It’s possible to examine the youngest
little girls kept in this position by a trusted adult on his arm. To visualize clearly the
hymenal ring, the little and big lips pull technique is used (b). In the genupectoral
position, the little girl leans on her hands and knees (c). This position is sometimes
less appreciated because the clinician stands behind her, out of her sight, but it’s
fundamental to confirm signs identified in the supine position [42]. To visualize
clearly the anus, a light traction is applied to the gluteus (d); the little and big lips
pull technique is used for the hymenal ring visualization even in the genu-pectoral
position (e).
It is important to know very accurately the ano-genital area anatomy of the pre-
pubertal girl, its anatomic variants, and the typical pubertal age estrogenization. The
vaginal orifice is surrounded by a tissue ring called hymen. The hymen and the anus
a b
c d
e
f
Fig. 13.2 (a, b) Supine position, (c–e) genupectoral position, (f) left lateral decubitus position
are described using the comparison with the clock quadrants (12 o’clock corre-
sponds to the suburethral zone and 6 o’clock to the rectum medial line in supine
position (Fig. 13.3a, b)).
a 12 o’clock
anterior labial commissure
urethral meatus
clitoris
hymen
9 3
hymenal meatus fossa navicularis
posterior labial commissure

6
fourchette
b 12 o’clock
prenianal folds
9 3
anal sphincter prenianal area
Fig. 13.3 Ano-genital area
In prepubertal girls, hymenal tissue can be completely absent in the suburethral

area approximately from 10–11 o’clock to 1–2 o’ clock. The posterior tissue portion
can be more or less represented thus the posterior edge can be more or less high,
configuring crescentic hymen, a frequent configuration. In another common hymen
configuration, the tissue completely surrounds the vaginal orifice (annular hymen).
The hymen, like the other genital organs, is under the sexual hormones influence.
The estrogens, for example during neonatal (due to mother hormones’ presence)
and puberal period, make hymen tissues more redundant, in a way that often fold on
themselves making edges wavy and frequently covering vaginal orifice.
The myth the hymen “breaks up” during the first sexual intercourse leads to the
preconception that it’s possible to determine whether there has been sexual activity
at least ones with the medical examination; actually, it is evident that health profes-
sionals without specific experience often expect that penetrative acts always leave
clear physical signs and believe that a doctor can determine through the medical
examination if an adolescent is “virgin” or not [43, 44].
In this regard, Kellogg’s review on 36 pregnant adolescents is very interesting:
only 2 of the 36 girls presented hymenal complete transection1 of the posterior half.
The scientific explanation is that penetration doesn’t always cause visible tissue
damages and/or that acute injuries can heal without leaving any sign.
13.8 Medical Examination Timing
Sexual abuse often doesn’t produce evident signs and many of the injuries are
superficial. For this reason, it is fundamental to perform the medical examination as
soon as possible. Literature recommends to carry out the examination within 72 h
from the sexual abuse or anyway as soon as the minor protection safety measures
have been applied.
Latest studies indicate the need to perform the medical examination in prepuber-
tal girls within 24 h from the event and within 72 h in adolescents. Furthermore, still
for prepubertals, it has been confirmed that DNA research provide positive results
especially when the medical examination is executed within 24 h [30].
The early medical examination objectives are numerous [25, 27, 33]:
• Identify ano-genital injuries and sexually transmitted diseases

• Prevent pregnancies through emergency contraception in pubescents
• Collect evidences for forensic medicine purpose
• Safeguard victim’s physical integrity and psychological wellness reassuring on
her health state
Medical examination should be postponed only in case the girl is not cooperative
and she doesn’t agree with the exam execution despite the reassurances. We restate
that the doctor who is going to perform the clinical examination must have specific
competences. In case a competent professional isn’t available, it’s recommended to
send the child to the closest specialized hospital or territorial center [30, 34, 45].
13.9 Injures Recovery Time
Traumatic ano-genital injuries heal rapidly, often leaving no trace [46].

The more often damaged structures during a penetrative sexual abuse are the
hymenal membrane, the fossa navicularis, and the fork [47].
Clefts/notches up to hymenal base are known as transections.

1
The healing process of these injuries is not different from the recovery of any
other injuries of the same nature in other body regions. The healing stages consist
of:
• Thrombosis and inflammation cells activation

• Damaged cells regeneration
• New cells multiplication
• New epithelium differentiation
The healing process of the more superficial injuries proceeds with formation of
new epithelium at a rate of 1 mm in 24 h. For deeper injuries, the damaged cells
regeneration process is fully active between 48 and 72 h, and the multiplication and
differentiation processes begin from the fifth and seventh day. The complete tissue
recovery takes from 4 to 6 weeks; the scarring tissue maturation might need at least
60–180 days [33, 47, 48].
These healing processes explain the usual absence of genital injuries in little girl
victims of sexual abuse if the medical examination is performed too far in time from
the last suspected violence episode.
13.10 Physical Signs
The evaluation of possible signs of sexual abuse can be accomplished during the
medical examination performed for other reasons or asked by a parent reporting a
suspect. In this case, it is the doctor’s duty to activate the services and/or report to
the Court according to the state legislation in the different countries.
Physical signs in case of sexual abuse are caused by traumas, mechanical actions
characterized by rubbing, stretching, and compressing. The sexual trauma effects,
and thus physical signs, can be: bruises, hematomas, abrasions, grazes, injuries.
Generally speaking, this signs vary depending on several factors [21, 46, 47, 49]:
• Abusive action type

• Force used
• Girl’s age and pubertal status
• Abusive events frequency
• Elapsed time from last abusive episode
It is fundamental to reaffirm that in the majority of cases, anal and genital inju-
ries become undetectable in a short time period from when they have been produced
and consequently it’s very recurring that injuries are not detectable anymore, not
because the episode didn’t happen but because the healing process leaves no cues.
Thus, conclusions that exclude with absolute certainty that the event happened must
be avoided [50–52].
The doctor can rarely formulate a definitive diagnostic hypothesis based on the
objective examination alone; therefore, the diagnosis of sexual abuse must be
multidisciplinary to avoid, due to a wrong medical valuation, a not-guilty adult is

unfairly accused or a minor victim of abuse isn’t safeguarded by the abuser
[53–56].
The observed signs have more or less probative consistency through the integra-
tion with other acquired evidence findings [25, 57].
Many studies demonstrate that 90–95% of children who declared in believable
way they have been abused have normal clinical finds or not specific physical signs.
In fact, the answer to the question “Has the girl been abused?” it is not usually on
the body [27, 33, 58].
Related to the physical signs only, several indications are provided by scientific
literature and the classifications proposed can lead to the correct interpretation of
what is observed during the medical examination [21, 30].
The evaluation path for a little girl victim of sexual abuse (Fig. 13.4) is complex
and must be anyway complete and multidisciplinary.
13.11 Sexually Transmitted Infections
Victims of child sexual abuse are at risk of contracting sexually transmitted infec-
tions (STI), even though the transmission is quite rare, due to the modalities that
characterize the majority of sexual abuses.
Actual literature does not recommend an STI screening for all the victims of
sexual abuse, but it is necessary to be able to evaluate how and when to proceed with
further diagnostic exams (Fig. 13.5).
It is recommended to submit to screening the little girls with anal and/or vaginal
penetration history, those living in high STI prevalence area, those who have been
abused by a stranger or by a high STI risk person keeping in mind the elapsed time
from the contact, the incubation time, and the window period.
Screening is also mandatory for little girls who have been diagnosed an STI in
the past and for those presenting suggestive STI signs and symptoms, such as vagi-
nal discharge, vulvovaginitis, genital ulcers, or condyloma acuminata [59].
The risk of contracting a sexually transmitted disease is related to the infection
prevalence itself in the local adult population, to the abuse modalities and dura-
tion, to the girl’s age, and to the possible coexistence of genital and/or perianal
injuries [60].
The type of exam and the examined area depend on the sexual contact modes and
are case-dependent: blood exams, pharyngeal, anal, vulvar, transhymenal or vaginal
swabs, or first urine exam.
Asserting that sexual abuse is the infection’s source with a certain degree of con-
fidence implies the consideration and exclusion of other possible transmission ways.
Many of the sexually transmittable infections can be vertically transmitted from
the mother to the child during pregnancy, the childbirth, or during the perinatal
period. For some others, it is exceptionally described that the transmission is through
fomite, by self-inoculation or for very close physical contact, with modalities vary-
ing from one infection to another.
Medical history
Possible information from Remote and recent

Girl and/or caregivers history
professionals, family, Police pathological anamnesis
Pay particular attention to genital-urinary and gastrointestinal symptoms,

and to behavioural alterations
Physical exam
Complete and detailed Tests Photographic

objective exam Blood tests documentation
Instrumental exams
Pharyngeal/vaginal/rectal swabs STI
Pay accurate attention to: Semen
— Erythema
— Oedema Weakly
— Vulvo-vaginal inflammation related to abuse
— Anal dilatation
— Bruises
Moderately
— Abrasions
related to abuse
— Cleft/notches in posterior half of non-fimbriated hymen
— Hymenal lacerations
Strongly
— Hymenal complete transection
related to abuse
— Hymenal tissue absence in posterior half
!
— STI
— Fourchette/perineal/perianal scars
— Semen detected on samples directly collected from the girl
Precisely report on medical chart each and every examination detail!
Differential diagnosis
Possible further specialist consultation:
dermatologist, oncologist, pediatrician,
Is the cause one of the following?

gynaecologist, haematologist and /or
Yes
Unlikely sexual abuse
– Anatomical form variations
– Systematic diseases
– Dermatological pathology
– Inflammatory processes No
Suspected sexual abuse
– Urethral prolapse
– Hemangioma
family doctor
– Accidental traumas
– Neoplasia
Multidisciplinary take in charge, case

discussion and possible minor
safeguard and therapeutic treatment
for the girl and her family if available.
– Social service – Judiciary authority

– Psychological service
Fig. 13.4 The evaluation path for a child victim of sexual abuse: medical history, physical exam
and different diagnoses
STI screening
When:
— Vaginal/anal penetration history
— Suspected abuse by a stranger
— Suspected abuse by a person at risk of STI
— STI suggestive symptoms
— STI remote history
— Living in STI high prevalence areas
STI testing
— Blood tests
— Pharyngeal/vaginal/rectal swabs (culture/NAAT* exams)
— First urine exam (culture/NAAT* exams)
* NAAT: Nucleic acid amplification test
Test results
Positive Negative
— Condyloma acuminata
Moderately
— Genital herpes simplex related to abuse
— Mycoplasmas
— Chlamydia Trachomatis
Strongly
— Neisseria gonorrhoeae related to abuse
— Trichomonas vaginalis
— Syphilis
— HIV
!
Yes Sexual abuse cannot be excluded:

further evaluation
Vertical transmission ?
No Suspected sexual abuse
Fig. 13.5 Sexually trasmitted diseases and child sexual abuse

We remind that while taking in charge a little girl victim of suspected sexual
abuse, it is also to be considered the possibility to submit to screening her brothers
and sisters (possible victims of abuse as well) too, the parents (to check vertical
transmission too) and any possible cohabitants.
Scientific evidences do not help to determinate at which age the vertical trans-
mission can be excluded and there is no research study providing a defined cut-off
age after which it cannot be considered.
From the literature analysis results the following:
• Gonococcal anal and genital infections are rarely acquired in perinatal age and
beyond the neonatal period and are considered as probable sexual abuse conse-
quences [21, 30, 61].
• Chlamydia infections in children older than 3 years have to be considered as a
probable consequence of sexual abuse [21, 30, 62].
• HIV infections in children not exposed to the virus in perinatal age, with no pre-
vious contacts with blood products or needles have high probability of being
consequences of sexual abuse [30, 62].
• Trichomonas has to be considered as possible consequence of sexual abuse
[21, 62].
• Herpes and condyloma acuminata can be sexually transmitted to children but are
not diagnostic of abuse by themselves and experts’ opinions are controversial
[30, 62].
• The mycoplasmas’ presence is also controversial [63].
The vertical transmission must always be considered, but we remind that sexual
abuse can happen at any age, even in infants. It is then important to highlight that
the identification of a vertically transmitted infection does not necessarily exclude
that the child could have been a victim of sexual abuse.
Literature studies indicates that, when the vertical transmission can be excluded,
Gonorrhea, Chlamydia, Trichomonas, Pox, Condyloma acuminata and HIV are
found more frequently in victims of sexual abuse than in non abused population.
Sexual abuse is the most probable transmission modality of sexually transmitted
infections in prepubertal girls [21, 30, 62].
We underline that the meaning of a sexually transmitted infection in a prepuber-
tal girl with history of suspected sexual abuse requires a careful interpretation and
always needs the urgent activation of the childhood protection services.
The answer to the question “is the presence of a sexually transmitted infection in
young girls a consequence of a sexual abuse?” is “almost always”.
“Almost always” is supported by literature and international guidelines, but
almost is a qualifying adjective that admits the possibility of rare or unusual trans-
mission mechanisms that don’t involve sexual abuse. So, in any case, the certainty
in concluding that a little girl has been or not sexually abused depends on the quality
of the path to make the diagnosis [64].
This path always must guarantee an expert professional intervention, a high
quality laboratory analysis, including taking samples correctly. Furthermore, it is
important to pay great attention to the safety and wellness of the girl and her fam-
ily through a multidisciplinary care with excellent communication flows between
institutions and a continuous comparison among professionals avoid achieving
easy and rushed conclusions, both supporting or against the sexual abuse hypoth-
esis [21, 30].
13.12 Documents
It is fundamental to collect all the medical examination data precisely and correctly
in the medical report. Terms and words must be not ambiguous or results of self-
interpretation, especially regarding the minor’s and caregivers’ history. It is recom-
mended to report the exact words used by the minor telling her history, transcribing
them in inverted commas.
The photographic data collection should be a standard procedure, especially in
case of evident physical injuries, due to its low frequency even when the sexual
abuses have been confirmed. The photographic data are fundamental to support the
clinical examination and to avoid submitting the little girl to multiple repeated
examinations in case of doubtful injuries. Moreover, they allow successive analysis
by other specialists, when injuries are already healed [21, 27, 30, 58, 65].
We reaffirm the importance of asking for girl’s agreement before performing any
act, including the photo shots.
Data to be collected and reported in the medial report are:
• Child and accompanist’s personal data

• Reason why the medical examination is asked for
• Minor and accompanist’s tell
• Familiar, physiologic, remote pathological, and recent pathological medical
history
• General and genito-anal exam examination
• The photographic material
• Minor’s behavior during the medical examination
• Instrumental/laboratory tests and specialists consultation if executed
• Possible therapy and preventive care
The medical report, based on the specific country legislation, in case of sexual
abuse has to be sent to the judiciary authority and/or to the childhood protection
services for the multidisciplinary care.
The detection, diagnosis, taking in charge, and treatment of sexual abuse con-
stitute complex problems where medical, psychological, social, and juridical
aspects intersect each other; this makes the involvement of many professional
roles indispensable and therefore the only possible and adequate tool to face
them is the teamwork made of professionals with specific competences on child
sexual abuse.
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Sexually Transmitted Diseases
in Adolescence 14
Gilda Di Paolo
Abbreviations
BV Bacterial vaginosis
DES Diethylstilbestrol
CDC Centers for Disease Control and Prevention
CIN Cervical intraepithelial neoplasia
ELISA Enzyme-linked immunosorbent assay
FTA-ABS Fluorescent antibody absorbed treponemal
HBV Hepatitis B virus
HCV Hepatitis C virus
HIV Human immunodeficiency virus
HPV Human papillomavirus
HSV Herpes simplex virus
LGV Lymphogranuloma venereum
MSM Men who have sex with men
NAAT Nucleic acid amplification test
RPR Rapid plasma reagin
SIL Squamous intraepithelial lesion
STD Sexually transmitted disease
STI Sexually transmitted infection
TP-PA T. pallidum particle agglutination
VDRL Venereal Disease Research Laboratory
VIN Vulvar intraepithelial neoplasia
G. Di Paolo, M.D.
Pediatric and Adolescent Gynecology Service, UOSD of Gynecology and Obstetrics,
Santo Spirito Hospital, Pescara, Italy

212 G. Di Paolo
The term “Sexually transmitted diseases” (STDs) refers to a variety of clinical syndromes
and infections that involve a great number of people all over the world [1, 2] and are
caused by pathogens that can be acquired and transmitted through sexual activity [3].
Symptoms related to the infection usually involve the genitalia and urinary tracts, but
there are some conditions that may have systemic manifestations.
The World Health Organization’s fight against sexually transmitted diseases
which is among the main concerns of worldwide public health [4]:
• 499 million curable sexually transmitted infections (gonorrhoea, chlamydia,

syphilis, and trichomoniasis) are diagnosed in patients between 15 and 49 years
old every year, many of which may be asymptomatic.
• Around 2/3 of these occur in under 25s
• At least 1 in 20 adolescents contracts STDs each year and the average age of
infection is decreasing in relation to the ever younger age of first sexual inter-
course in early adolescence (already 7% between 13 and 14 years old) and in
relation to the increasing number of occasional partners.
• USA: 20 million new STDs are diagnosed each year, 50% among 15–24 year
olds (mainly gonorrhoea and chlamydia)
• STDs represent one of the main reasons of both male and female infertility
(USA: each year undiagnosed STDs cause infertility in 24,000 women)
• Drug resistance (especially in gonorrhoea) represents a great challenge for the
overall control of the STDs in the world
The possibility of contracting an STD in young women is particularly high both

due to the biological risks of the age group and due to the behaviour of adolescents
(Table 14.1).
The biological vulnerability of the STDs in adolescents is related to:
• The immaturity of the immune system with lower local production of IgG and
IgA
• Less dense cervical mucus due to the lack of progesterone as a consequence of
anovulatory cycles
• Physiological extension of the columnar epithelium from the cervical canal to
the vagina, with a higher susceptibility of the cylindrical cells to the STDs
• Alteration in vaginal flora caused by menstruation, use of contraceptives, vaginal
douching, antibiotics, sexual intercourse, and stress
Factors of adolescent behaviour which expose them to greater risk of contracting

an STD include:
• The ever younger age at which they have their first experience of sexual
intercourse
• Promiscuity
• Number of sexual partners
14 Sexually Transmitted Diseases in Adolescence 213
Table 14.1 Sexually transmitted pathogens and related infections

Aetiological agents Infection, disease, or related syndrome
Bacteria
Calymmatobacterium Inguinal granuloma
granulomatis
Chlamydia trachomatis Urethritis, cervicitis, epididymitis, proctitis, pharyngitis,
MIP, lymphogranuloma venereum, neonatal conjunctivitis
Gardnerella vaginalis Vaginitis, urethritis
Haemophilus ducreyi Chancres ulcers or chancroid
Neisseria gonorrhoeae Urethritis, cervicitis, epididymitis, proctitis, pharyngitis,
conjunctivitis, neonatal conjunctivitis, MIP
Mycoplasma genitalium Urethritis, cervicitis
Streptococcus type B Vaginitis, balanoposthitis
Treponema pallidum pallidum Syphilis
Ureaplasma urealyticum Urethritis, prostatitis, MIP
Virus
Cytomegalovirus (CMV) Congenital malformations
Herpes Simplex Virus-HSV1 Primary and recurrent genital herpes, neonatal herpes
and 2
HAV, HBV, HCV Acute and chronic viral hepatitis
Human papillomavirus Genital warts, cervical and anal dysplasia
Molluscum contagiosum Molluscum contagiosum
virus-Pox
HIV-1 HIV disease/AIDS
Zika Virus Microcephaly, neurological complications
Protozoa
Entamoeba histolytica Amebiasis
Giardia lamblia Giardiasis
Trichomonas vaginalis Vaginitis, urethritis, prostatitis, epididymitis
Ectoparasites
Phthirus pubis Pediculosis pubis
• Oral sex [5]

• Abuse of drugs and alcohol
• Smoking
• Failure to use any form of protection
• Limited use and/or negative perception of the health service [6]
• Inadequate knowledge and/or awareness of STDs
14.1 Chlamydia trachomatis Infection
Chlamydia trachomatis is the most common cause of curable bacterial sexually

transmitted infection (STI) worldwide. Prevalence is higher among under 24s and in
most cases is an asymptomatic infection (75% in women, 30% in men) and for this
reason there is widespread transmission of the disease.
214 G. Di Paolo
Chlamydia trachomatis is an obligate intracellular parasite of which 18 serologi-

cally distinct variants exist (these have been categorized by identifying monoclonal
antibodies). These serotypes are:
• Serotypes A, B, Ba, and C cause ocular trachoma, a major cause of blindness in

many developing countries.
• Three serotypes L1, L2, and L3 are associated with lymphogranuloma venereum.
• Serotypes B, D, E, F, G, H, I, J, and K are associated with infection of the genital
tract—cervicitis, urethritis, salpingitis, proctitis, and epididymitis. Major com-
plications of female genital tract disease include acute pelvic inflammatory dis-
ease, ectopic pregnancy, infertility, and infant pneumonia and conjunctivitis.
Chlamydia is spread by sexual contact (vaginal, anal, or oral sex) and as vertical
transmission at birth from mothers to infants.
The higher the number of sexual partners is, the greater the risk of contracting
the infection is.
Indeed, the principal risk factor for contracting Chlamydia is having had a new
sexual partner in the last 6 months.
Any clinical symptoms appear 1–3 weeks after infection. In women, Chlamydia
infects the cervix, and, in most cases, the urethra, causing vaginal discharge, coital
bleeding, and dyspareunia. On physical examination, mucopurulent or purulent dis-
charge from the endocervical canal and cervical friability are common (Fig. 14.1).
In an elevated number of cases, the infection can involve the urethra and the symp-
toms are characterized by dysuria, bladder tenesmus, and urinary frequency.
Infection can cause pelvic inflammatory disease with abdominal pain, fever, back-
ache, intermenstrual bleeding, and possible persistent fallopian tube damage.
Fig. 14.1 Mucopurulent

or purulent sichard from
the portio (Chlamydia
infection)
Men may act as disease carriers, spreading the condition, but rarely developing
long-term health problems. Infection could be silent for months or years. In this
case, the condition may be identified during a screening programme and/or rou-
tine testing. In men, chlamydia infection causes urethritis and epididymitis (from
30 to 50% of non-gonococcal urethritis is caused by chlamydia). The symptoms
are dysuria and discharge when squeezing urethral meatus. If the infection is
transmitted by anal sex, the symptoms are characterized by proctitis with pain and
bleeding. If the transmission is by oral sex, the manifestation is a pharyngeal
infection.
Despite the fact that symptoms are tolerable and are often not diagnosed, the
consequences for the reproductive organs, and especially for women infected with
Chlamydia, may be very serious. Untreated chlamydia infections put women at an
increased risk (40–67%) of developing pelvic inflammatory disease. The involve-
ment of the fallopian tubes, the uterus, and of other adjacent tissues can cause per-
manent damage (tubal occlusion being the worst possible consequence), or lead to
peri-hepatitis (Fitz-Hugh-Curtis syndrome). Additional negative outcomes include
chronic pelvic pain, tubaric infertility, and ectopic, or “extra-uterine”, pregnancy.
Tropism from Chlamydia in the cylindrical epithelial cells of the endo-cervix causes
an inflammatory reaction which attracts polymorphonucleated cells and conse-
quently leads to the development of a humoral immune response. Replication of the
micro-organism in the host leads to cellular lysis with associated tissue damage
which is worsened by the immune response. Several studies demonstrated that tubal
damage pathogenesis is prevalently caused by the host immune reactivity, and, in
particular, by the prolonged production of cytokine and chemokine by the tubaric
epithelium. Immune reaction reactivation, is also possible, however, in the case of
persistent infection, or re-infection, which trigger fibrotic responses towards
Chlamydia antigens, among which is the Hsp60 (CT-Hsp60) protein which shares
common amino acid sequences with man and with other bacteria, such as Escherichia
coli [7].
In men, permanent damage seems less probable, although Reiter’s syndrome has
a higher incidence, which is a form of sero-negative arthritis that includes skin
lesions, urethritis, and iridocyclitis.
Chlamydia infection may also increase susceptibility to HIV, which, in adoles-
cents, has been shown to increase by a factor of 5. Moreover, a persistent Chlamydia
infection can increase the risk of infection by oncogenic types of HPV, thus increas-
ing the risk of cervical cancer [8, 9].
Urogenital infections caused by Chlamydia may be diagnosed using endocervi-
cal tampon samples (in women) and endo-urethral tampon sample (in men) or by
testing “first emission” urine samples.
Nucleic acid amplification tests (NAATs) are the most sensitive tests and are
recommended for detecting Chlamydia trachomatis infection [10].
NAATs can be performed on endocervical, urethral, vaginal, pharyngeal, rec-
tal, or urine samples. The accuracy of NAATs on urine samples has been found
to be nearly identical to that of samples obtained directly from the cervix or
urethra [11].
216 G. Di Paolo
Treating Chlamydia infections prevents adverse reproductive health complica-

tions and continued sexual transmission, and treating their sexual partners can pre-
vent re-infection and infection of other partners.
Recommended treatment:
• Azithromycin 1 g, orally in a single dose
Or
• Doxycycline 100 mg, orally, twice a day for 7 days
Alternative treatment:
• Erythromycin 500 mg, orally, four times a day for 7 days
Or
• Erythromycin ethyl succinate 800 mg, orally, four times a day for 7 days
Or
• Levofloxacin 500 mg, orally, once daily for 7 days
Or
• Ofloxacin 300 mg, orally, twice a day for 7 days
A meta-analysis of 12 randomized clinical trials of azithromycin versus doxycy-

cline for the treatment of urogenital chlamydial infection demonstrated that the
treatments were equally efficacious, with microbial cure rates of 97% and 98%,
respectively [12].
A high prevalence of Chlamydia trachomatis infection has been observed in
previously treated patients. Most of these post-treatment case are not due to the
inefficacy of the treatment, but rather, are usually caused by re-infection follow-
ing unprotected sexual intercourse with, either, an inadequately treated partner, or
with a new, partner who is also infected. For this reason is very important to treat
the partner, or partners, whether or not they are asymptomatic, and, even, follow-
ing a negative test. Complete abstention from sexual activity is recommended
until 7 days after therapy with single-dose azithromycin or until after treatment
with doxycycline has been completed. The use of barrier contraception (e.g. a
condom) significantly reduces the risk of transmission but does not eliminate it
completely. Given the wide diffusion of asymptomatic Chlamydia infections, an
annual chlamydia screening programme would be opportune for sexually active
women below the age of 25, as well as for all sexually active women with frequent
new or multiple sexual partners, having a partner with a sexually transmitted
infection, and for all pregnant women. In some European countries, the annual
report of the National Chlamydia Screening Programme has registered a reduc-
tion in the episodes of pelvic inflammatory disease [13, 14].
14.2 Lymphogranuloma Venereum
It is a sexually transmitted infection caused by some serotypes of Chlamydia tra-

chomatis (L1L2L3,) which cause a chronic disease. It is endemic in Asia, Africa, and
South America and was observed among male homosexuals in Europe (especially if
infected HIV), where is a relatively common cause of proctitis [15–17].
The heterosexual transmission has been attributed to asymptomatic women car-
riers whereas in male homosexuals, the asymptomatic rectal infection is the likely
source of transmission [18]. The contagion can only be contracted through vaginal,
oral, and anal sexual intercourse. The infection is manifested by a vesicle in uro-
genital or rectal region that may erode, with the formation of a small painless ulcer
that heals in a week with no results, and that often goes unnoticed. In the next phase,
for the spread of the bacterium in the lymphatic system, the typical symptoms are a
unilateral lymphadenitis (potentially involving the iliac, perirectal, and inguinal
lymph nodes) associated with fever, malaise, and arthralgia. If not treated in good
time, the infection may complicate with peri-rectal abscesses, fistulas, and scars that
requiring surgery.
The diagnosis of lymphogranuloma venereum is based on history, on epidemiologi-
cal information, after excluding other clinical conditions of proctitis, lymphadenopa-
thy, and rectal ulcers; it is confirmed by the identification of the type-specific DNA
LGV, if you detect Chlamydia trachomatis, and rectal levy is the best procedure.
Treatment [19]
• Doxycycline 100 mg orally two times daily for 21 days
• Erythromycin 500 mg orally four times a day for 21 days
• Was proposed azithromycin in single or multiple doses
14.3 Chancres Ulcers or Chancroid
It is an infection caused by Gram-negative bacillus Haemophilus ducreyi, rare in

Europe, but particularly common in tropical countries, although the prevalence of
chancroid appears to have decreased worldwide. Transmission occurs as a result of
a trauma during sexual intercourse, and after an incubation period of about 3–10
days, the infection is manifested by the appearance of a papule with erythematous
edge on the skin or on mucosal of the genitals. After about 24–28 h, the papule
develops first in pustule and then in soft, bleeding, and painful ulcer. Clinically, an
inguinal lymphoadenopathy and general symptoms may be associated. The combi-
nation of painful genital ulcer with inguinal adenopathy suppurative could be indic-
ative of chancroid, especially after excluding other diseases responsible for genital
ulcers (syphilis, herpes, lymphogranuloma venereum); the diagnosis can be con-
firmed by identifying the H. ducreyi even if the culture is difficult to perform [20].
218 G. Di Paolo
As with other sexually transmitted infection leading ulcers in the genitals, the
chancroid increases the risk of HIV transmission, and therapy in HIV-infected sub-
jects is more complex.
Recommended treatment regimens [21]:

Azithromycin 1 g orally in a single dose
or
ceftriaxone 250 mg IM as a single dose
or
Ciprofloxacin 500 mg orally two times daily for 3 days
Sexual partners should also be treated even in e absence of clinical
manifestations.
14.4 Gonorrhoea
Gonorrhoea is a sexually transmitted disease caused by infection with the Neisseria

gonorrhoea bacterium. The incubation period varies from 3 to 10 days. N. gonor-
rhoea infects the mucous membranes of the reproductive tract, including the cervix,
uterus, and fallopian tubes in women, and the urethra in women and men and can
also infect the mucous membranes of the mouth, throat, eyes, and rectum. The
organism adheres first to the epithelial cells, infects the epithelial layer, then pene-
trates into the sub-epithelial space, initiating the inflammatory process and its com-
plications. Trans-luminal spread in males can lead to prostatitis orchiepididymitis
and in females leads to PID (10–20% of the cases) and peritonitis. The bacterial
dissemination can also cause bacteraemia, cutaneous lesions, fever, arthralgia,
arthro-synovitis, especially of knee, hip, and wrist. Transmission can occur through
sexual contact with the penis, vagina, mouth, or anus of an infected partner.
Gonorrhoea can also be spread perinatally from mother to baby during childbirth.
Highest reported rates of infection are among sexually active teenagers and young
adults (15–29 years old). Gonorrhoea infection, in particular, is also concentrated in
specific geographical locations and communities. Subgroups of MSM are at high
risk of gonorrhoea infection.
Asymptomatic infection of the genital tract is very frequent in women, occurring
in about 90% of cases, and does occur in males, but in only about 5% of cases.
Rectal and pharyngeal infections are generally asymptomatic.
In women, symptoms are generally correlated with endocervical and urethral
infections and include an increase or a variation in the characteristics of vaginal
secretions, intermenstrual spotting, dysuria, menorrhagia, dyspareunia, muco-
purulent urethral or cervical discharge. Gonorrhoeal infection should be excluded
proactively in young females presenting with lower abdominal pain, pain during
uterus and adnexa mobilization and in women with a significant sexual history.
Pelvic inflammatory disease is thought to affect one in five women who remain
untreated for gonorrhoea. The gonococco bacterium can cause Bartholin’s

abscesses and can lead to inflammation of the para-urethral glands. In males,
gonorrhoea infection generally causes acute urethritis, displaying profuse muco-
purulent urethral discharge, dysuria, and meato-urethral erythema [22, 23].
The diagnosis is based on the identification of N. gonorrhoea in genital, rectal,
pharyngeal, and ocular secretions [10].
Culture testing is a cheap, specific diagnostic test which permits rapid identifica-
tion of the bacteria and also permits testing for antibiotic susceptibility. The use of
selective culture terrains with the addition of antibiotics is recommended. Culture
testing is recommended for samples which have been taken from the endocervix,
urethra, rectum, and pharynx, and samples should be taken according to the infor-
mation contained in the sexual anamnesis of the girl. The sensibility of culture test-
ing is elevated for samples taken from the genital area as long as collection, transport,
and storage of the sample itself are appropriate.
Instant microscopic evaluation with Gram, or methylene blue has good sensitivity
(>95%), and good specificity, as a rapid diagnostic test in symptomatic men with ure-
thral secretions. Microscopy has poor sensitivity (<55%) in asymptomatic men and in
identifying endocervical infections (<55%) or rectal infections (<40%). Microscopic
evaluation cannot be recommended as a diagnostic test in these circumstances.
Nucleic acid amplification tests (NAATs) for the detection of Neisseria gonor-
rhoeae have a sensitivity >95% compared with microbiological culture although
sensitivity varies from one type of NAAT to another. In the case of confirmation of
diagnosis, or on failure of therapy, an antibiogram culture should be performed.
NAAT can be used on endocervical swabs, vaginal swabs, urethral swabs, and urine
samples. In women, NAAT sensitivity on urine is lower than that of NAAT per-
formed on endocervical and vaginal swab. A single vaginal or endocervical speci-
men evaluated with NAAT has a sufficient sensibility (90%) when used as a
screening test. Collection of urethral, urine, rectal, and pharyngeal specimens
should be directed by the anamnesis and from the personal sexual habits.
Test indications:
• Vaginal discharge associated with risk factors for STD (<30 years old, new or
multiple sex partners)
• Mucopurulent cervicitis
• Sex partner who has been recently diagnosed with an STD or a PID
• Symptoms or signs of urethral discharge in males
• Acute orchiepididymitis in males <40 years old
• Acute PID
• STD screening in adolescents
• Screening for subjects with multiple sex partners
• Purulent conjunctivitis in newborns.
Gonorrhoea treatment is complicated by the ability of Gonorrhoea to develop

resistance to antimicrobials, and this causes grave limitations to the therapeutic
approach [24, 25].
220 G. Di Paolo
However, there is a geographical variability of the diffusion of the resistant types.

For this reason, it is useful to consider different therapeutic options established by
the national surveillance system.
In Europe, cephalosporins are mainly used because of the recurring resistance of
N. gonorrhoea to fluoroquinolones.
Recommended treatment
• Ceftriaxone 250 mg IM, in a single dose
or
• Cefixime 400 mg, orally, in a single dose.
Increasing bacterial resistance also extends to these antibiotics and makes it

essential, whenever persistent symptomatology is encountered, to repeat microbio-
logical culturing with antibiogram of the isolated strain.
The Centre for disease control recommended a possible dual therapy by the addi-
tion to Ceftriaxone of Azithromycin 1 g, orally, in a single dose. Recent sex partners
(i.e., persons having sexual contact with the infected patient within the 60 days
preceding onset of symptoms, or gonorrhoea diagnosis) should be referred for eval-
uation, testing, and for treatment.
The therapy must be extended to any partners with the strong recommendation to
abstain from any sexual activity until the therapy has been completed and the symp-
toms have disappeared.
All new cases of N. gonorrhoea infection should be notified to local, regional,
and national authority.
14.5 Syphilis
It is a complex sexually transmitted infection caused by the bacterium Treponema

pallidum.
It develops in several stages, each characterized by different symptoms and
course and is considered a chronic systemic disease marked by alternating active
phases and periods of latency.
According to data provided by the WHO, there is an increased prevalence of
syphilis in the general population, and men are affected more than women.
Transmission is by sexual contact or by vertical, mainly transplacental (congeni-
tal syphilis).
14.5.1 Primary Syphilis
From infection, the onset of symptoms may take 10–90 days (average 20 days).The
first stage is characterized by the appearance of a papule at the place where the bac-
terial infection occurs (vulvar region, cervix, mouth, penile, anal canal), which later
after abrasion becomes an ulcer with raised edges, which are not painful (syphi-
loma) and which heals spontaneously after 3–6 weeks. If the infection is not treated
at this stage, it progresses to the secondary stage.
14.5.2 Secondary Syphilis
Begins, about 2 months after the healing of the syphiloma, with the onset of rash
that affects the palms of the hands, soles of the feet or other body parts; these lesions
type macules, papules, or pustules are not associated with pruritus and are concomi-
tant with a systemic not painful lymphadenopathy. In the mouth and in the vulvar
region appear erosions painless but contagious. Characteristic of this stage are non-
specific general symptoms (fever, headache, weight loss, patchy alopecia, sore
throat). Even this stage may resolve spontaneously without any treatment.
14.5.3 Lag Phase
Stage without clinical manifestations is detected only by serology and the evolution
can be towards recovery, asymptomatic carrier state or tertiary syphilis.
14.5.4 Tertiary Syphilis
At this stage can begin internal organs damage (brain, nervous system, eyes, heart,
liver, bones, blood vessels). On the skin and mucosa appear painless papules that
evolve into ulcers and scarring (Syphilitic gumma). Tertiary syphilis occurs in not
treated subjects even after decades and is fortunately rare evolution.
The diagnosis of syphilis can be performed using material taken from a patient’s
excoriation or wound, isolating treponema, that is easily recognizable by optical
microscopy or with direct immunofluorescence techniques, reliable methods for the
diagnosis of early syphilis.
Serological diagnosis is based on using two types of tests: non-specific and spe-
cific for treponema. Among the first, there are the Venereal Disease Research
Laboratory (VDRL) that identifies cardiolipin antibodies; it becomes positive after
3–4 weeks after infection, becomes negative after therapy, and is used to evaluate
the effectiveness of treatment, and rapid plasma reagin (RPR); the specific trepo-
nema tests are the Fluorescent Antibody Absorbed treponemal (FTA-ABS) and T.
pallidum Particle Agglutination (TP-PA).
The non-specific tests are widely used as inexpensive, but their use is not suffi-
cient for diagnosis since they can result in a false negative in patients tested during
primary syphilis and can result in a false positive in people without syphilis but
affected by other diseases: infectious (malaria, tuberculosis, viral fevers, leprosy),
collagen vascular disease, pregnancy, age, drug addiction. Therefore, the subjects
tested with a non-treponemal test should always be assessed with a treponemal test
to confirm the diagnosis. Specific tests positivity persists for all life.
222 G. Di Paolo
Recently, specific new generation tests like ELISA have become available for
use on a large scale.
The treatment is simple and involves the use of penicillin. Preparation, dos-
age, and treatment duration depend on the stage and clinical manifestations of
disease:
• Benzatin penicillina G 2.4 million in single dose IM in the first and second
stage and in early latent phase
• Benzatin penicillina G 2.4 million units IM three times, in latent syphilis
and in the third stage.
The treatment of primary and secondary syphilis in allergic subjects includes

an attempt to desensitization before using the drug of second choice,
Doxycycline (100 mg orally twice a day for 14 days) [26].
Since latent syphilis is not transmitted sexually, the goal of treating people in this
stage is the prevention of complications of disease and vertical transmission.
However, a careful examination of all accessible mucosa (oral cavity, perianal
area, perineum, vagina in women, and under the foreskin in men) should always be
performed in people with latent syphilis.
The infected person should refrain from any sexual activity with new partners
until complete wound healing. Shall be performed diagnostic tests and therapy on
sexual partners and, also, patients with primary and secondary syphilis should be
tested for HIV infection.
14.6 Bacterial Vaginosis
Bacterial vaginosis (BV) is among the most common causes of vaginal secretions of
reproductive age. It is characterized by an abundant proliferation of anaerobic bac-
teria (Gardnerella, Mycoplasma, Bacteroides, Mobiluncus, Atopobium) and a
reduction of the Lactobacillus normally found in the vagina with a consequent
increase in vaginal pH.
Bacterial vaginosis is not a sexually transmitted infection but it facilitates the
transmission of several (HIV, Gonorrhoea, Chlamydia, HSV-2). The vaginosis
appears most often after the first sexual intercourse, after having changed partners
and in case of multiple partners. Vaginosis risk factors are: the use of vaginal
douches and lubricants, dripping related to IUD, the cigarette smoke.
The complications of bacterial vaginosis are pelvic inflammatory disease, post-
surgery infections, and obstetric complications (late abortion, preterm delivery,
PROM, postpartum endometritis).
BV is the most frequent cause of malodorous leucorrhoea, but women with VB

have mostly no symptoms.
The diagnosis is based on the presence of at least three of the following clinical
manifestations. (Amsel criteria)
• Presence of whitish vaginal homogeneous secretions, which cover the vaginal

walls
• Vaginal pH > 4.5
• Presence of “clue cells” at microscopic examination of vaginal exudate samples
• Fish smell by whiff test (secretion on slide +10% KOH)
It is also possible to use the Nugent score, which consists in finding the depletion
of the normal Lactobacillus flora (It is assigned a score, which ranges from 0 to 10
and is based on the presence of different bacterial morphotypes observed on Gram-
stained smears; Lactobacillus (L), Gardnerella (G), and Mobiluncus (M) are
quantified).
Bacterial vaginosis requires treatment only in these cases: if it is symptomatic, if
it appears during pregnancy or before the insertion of an IUD or before a gynaeco-
logical operation.
Treatment
Metronidazole 500 mg × orally daily for 7 days
0.75% Metronidazole gel for intravaginal application (5 g) of the 2× for 7
days
Or
Clindamycin Gel 2% or from 100 mg ova for 7 days
Or as a second choice
Tinidazole os × (2 g × 2 days)
While taking metronidazole, alcohol must be avoided since it can provide

nausea, vomiting, abdominal cramps (disulfiram-like syndrome).
The use of probiotics and intestinal acidifying can rebalance the vaginal
flora [27].
The benefit of the therapy may also include a decrease in risk of acquisition of C.
trachomatis, N. gonorrhoeae, T. vaginalis, HIV, and HSV-2. In the presence of a
high colonization of Mycoplasma or Ureaplasma, it must be evaluated the associa-
tion with a specific therapy.
224 G. Di Paolo
14.7 Herpes Virus Infection
Genital herpes is a chronic viral infection. Two types of HSV may cause genital
herpes: HSV-1 and HSV-2; most cases of recurrence of genital herpes are caused by
HSV-2.
A higher percentage of ano-genital herpes infections are ascribed to HSV-1,
which is particularly evident among young and MSM women [28], as a conse-
quence of oral sex. In 50% of cases, infection is asymptomatic and, thus, favours the
diffusion of the virus.
The primary infection (first contact with the virus) is transmitted through close
cutaneous and mucosal contact and, thus, the virus may enter the epithelial cells and
replicate.
The symptoms of the infections, after a few days from the contact, are pain, vul-
var pruritis, vaginal discharge, burning sensation associated with the appearance on
vulva, anus, and cervix of vesicles, which rapidly form ulcerative lesions. Cutaneous
ulcerative lesions may be covered by scabs.
Generally, genital lesions are associated with satellite lympho-adenitis and a
global reduction in well-being. In some cases, lesions may involve only the cervix
(Fig. 14.2), and there may be cases in which clinical manifestations appear after
6–12 months after first infection.
In adolescence, in 20% of cases of herpes infection, pharyngo-tonsillitis infec-
tion is present.
After a few weeks, after the visible lesions have healed, the virus no longer
reproduces and it retreats through the peripheral terminations to the sacral ganglion
with an absence of symptoms (asymptomatic phase, or latent infection).
Recurrences appear when the viral replication is reactivated, which may be caused
in various ways, but above all by a weakening of the immune system of the host.
The diagnosis of genital herpes is mainly clinical, and the identification of spe-
cific antibodies is useful in case of primary infection (anti-HSV antibodies are
Fig. 14.2 HSV lesion of

the cervix
produced during the first weeks after the infection and persist) or in case of atypical
manifestations.
It is important that a differential diagnosis which considers other possible causes
of genital ulcers (cancroid, Crohn’s Disease, Lipschutz ulcers, Behcet’s disease,
pemphigus, secondary ulcers caused by pharmacological reaction).
HSV-2 infection leads to an increased risk of bacterial vaginosis. In particular,
this gives rise to an increased risk, about three times greater, of contracting HIV and
may accelerate the progression of AIDS.
Most pharmacological treatments involve the use of oral antiviral drugs that
inhibit the viral DNA polymerase of the HSV. Systemic therapy should be given
both in the case of primary infection, and in recurrences, but does not fully eliminate
the infection, nor does it reduce frequency. Once the treatment has been interrupted,
the risk, frequency, and the severity of recurrences is unaltered. Topical antiviral
drugs give poor results.
Maintenance of suppressive treatment, reduces the frequency of recurrence in
Recommended treatment for first clinical episode:

• Acyclovir 400 mg, three times/day for 7–10 days,
or
• Acyclovir 200 mg, five times/day for 7–10 days
• Famciclovir 250 mg, three times/day for 7–10 days
• Valacyclovir 1 g, twice/day for 7–10 days
Suppressive treatment:
• Acyclovir 400 mg twice/day
• Valacyclovir 1 g once/day
• Famciclovir 250 mg twice/day
patients that have had more than six episodes in a single year and also reduces the
risk of transmission to a partner.
In case of herpes virus infection, counselling is important in order to reduce the
risk of transmission; therefore, it is necessary for the patient to:
• Be informed of the nature and course of the disease, of the possibility of recur-
rence, and of the risk of transmission even in asymptomatic phases
• Inform the partner of the presence and potential infection of the disease
• Recognize recurrence and avoid sexual activity during that phase
• Use a condom during any kind of sexual activity and, be aware that, if used cor-
rectly, a condom can reduce the risk of transmission
• Be informed of the therapies available in order to prevent or reduce the possibil-
ity of recurrence
226 G. Di Paolo
14.8 Human Papillomavirus
Human papillomavirus (HPV) is the most common sexually transmitted viral dis-
ease: about 111 million new cases/year in younger under 25 years old. Approximately
150 types of human papillomavirus infection (HPV) have been identified by
genome, at least 40 of which can infect the genital area [29], other types present a
specific tropism for the oropharyngeal and laryngeal area or for the skin. The differ-
ent types of HPV are separated into high- and low-risk types for malign transforma-
tion: some are responsible for benign transformations (condilomatosis,
papillomatosis), whereas others produce pre-invasive lesions (dysplasia) and inva-
sive lesions (tumours). Two types of HPV (HPV16 and 18) cause 70% of the
tumours of the neck of the uterus and precancerous cervical lesions; there is also
evidence to link HPV with tumours of the anus, the vulva, the vagina, the penis, the
head, and the neck (tongue, tonsils, and throat).
HPV 16 is the most frequent virus type and is diagnosed in about 30% of all the
HPV infections; it is associated to cervical carcinoma, both as squamous cell carci-
noma and adenocarcinoma. It is also associated to 90% of vulvar intraepithelial
neoplasia (VIN) and 85% of vaginal, anal, and oropharyngeal cancers.
HPV is transmitted sexually through contact with skin and mucous membranes
and the micro-traumas which occur during sexual intercourse could favour trans-
mission. Infection may also occur just through genital contact, and it is important to
know that the use of a prophylactic does not totally eliminate the risk of infection if
the virus has infected the skin area which is not protected by the condom [30]. In
rare cases, vertical transmission may occur (from infected mother to baby during
birth) or self-contamination may spread the infection to other parts of the body.
Transmission by fomites has been hypothesized (as indirect transmission on towels,
diagnostic instruments, and underwear) although to what degree the virus is able to
survive outside the body, and its consequent capacity to infect, is not known.
Risk factors for HPV transmission and infection are [31]:
• Young age at first sexual intercourse

• Multiple sexual partners
• Sexual intercourse without using barrier methods
• Immunodeficiency condition
• Partner with high risk for STD.
Most genital HPV infections (70–90%), whether caused by low-risk or high-risk

type HPV, are transient, asymptomatic, and have no clinical consequences. The rea-
son is that the immune system can remove the virus before it causes pathogenic
damage. In fact at 18 months from infection, 80% of women become HPV negative
[32], and this percentage is higher in adolescents.
There are three possibilities of evolution for the HPV infection: regression, per-
sistence, and progression.
It is hypothesized that, despite the apparent clearance, the virus can persist in the
epithelium with a small charge and the disease can recover again if the immune host
defences decrease.
The virus within the host cell can remain silent in episomal form; it can also
induce its replication through the proliferation of squamous epithelium and produce
vegetative form or it can integrate into the host cell genome, where it induces carci-
nogenesis processes.
The persistent (more than 18–24 months) HPV infection at high risk is the
most important risk factor for the development of high grade CIN or invasive
cancer.
Regarding host-related factors, these may include: alterations of immune status,
pregnancy and, especially in young women, the presence of both herpes virus infec-
tions 2 and Chlamydia, cigarette smoking (nicotine derivatives are concentrated in
the cervical mucus and act as immunosuppressants), the use of oestrogen-progestin
contraceptive pills which facilitates the persistence of HPV 16 virus (in addition to
reduction of the use of barrier methods).
The evolution of HPV infection to invasive cancer goes through lesions con-
fined to the epithelium-defined SIL (squamous intraepithelial lesions). SIL were
divided into:
• LSIL which includes the cytopathic changes of HPV infection and mild dyspla-
sia (CIN I) (Figs. 14.3 and 14.4)
• HSIL which includes moderate dysplasia, severe dysplasia, and carcinoma in
situ (CIN II, CIN III, CIS).
CIN (cervical intraepithelial neoplasia) is a histological term that considers the

epithelial involvement by the lesion. Then, depending on the severity, following
grades of CIN can be distinguished:
• CIN I The mild dysplasia: lesion involving the basal third of the epithelium
• CIN II moderate dysplasia: lesion involving up to 2/3 of the epithelium
• CIN III severe dysplasia: lesions involving the entire epithelium without exceed-
ing the basement membrane
Fig. 14.3 L-SIL of the

portio
228 G. Di Paolo
Fig. 14.4 H-SIL of the

portio
Fig. 14.5 Florid vulvar

condylomatosis
These lesions have all the opportunity to regress, those of low grade with a higher
percentage.
In adolescence, the most common clinical manifestation of HPV infection is
ano-genital warts (florid ano-genital condilomatosis) (Fig. 14.5).
Epidemiological studies have found a low-risk HPV DNA in 100% of ano-genital
condyloma, attributable in most cases to HPV 6 and HPV 11. The lesions appear
after about 2–4 months from infecting sexual intercourse. Concerned areas may be
vulva, vagina (Fig. 14.6), anus, the perineum, the urethra, and also the cervix.
Diagnosis of ano-genital warts is easily detectable with genital examination: the
lesions appear as white-pinkish growths, sometimes with the typical cauliflower
shape; they may be multiple and affect even large areas. It is necessary to resort to
the use of the colposcope in case of micro-warts (Fig. 14.7) or of sub-clinical lesions
or in suspected involvement of portio (Fig. 14.8). Normally, condilomatosi is
asymptomatic and the detection can be casual. The presence of itching, burning, and
vaginal discharge is caused by bacterial or fungal superinfection.
Fig. 14.6 Condylomatosis

vaginalis
Fig. 14.7 Vulvar

microwarts (evident only
with colposcopy)
Therapy for HPV depends on the type of wound that the virus determines and
from its seat; even if the benign genital lesions may resolve spontaneously, they
often require specific treatments. Those pathologies have multiple consequences in
teenager life: number of relapses, resistence to the therapies and scarrig sequelae
may have a negative psycological and sexual impact.
Genital warts can be treated with both medical and surgical therapies.
For vulval-perineal condylomatosis, cytotoxic and immunomodulating medi-

cation can be used:
–– Podophyllotoxin 0.5% solution, in two times per day × 3 consecutive days,

up to a maximum of 6 weeks.
–– Imiquimod, an application three times a week up to a maximum of 16 weeks
230 G. Di Paolo
One alternative is sinecatechin ointment (derived to 15% from green tea).
The surgical therapies are: diathermy, laser vaporization, cryotherapy with

liquid nitrogen.
It has been demonstrated that in young women (younger than 20 years old) there
is a predominance of low-risk HPV infections and in the cervical area are found
mainly paintings of condilomatosis and of low grade CIN, with risk of disease recur-
rence and not of progression; in fact, cervical cancer is very rare in adolescence.
Secondary prevention based on screening of cervical lesions is not recom-
mended in this age group, as a result of evidence shown in several studies that
cytological abnormalities detected in adolescents are predominantly low grade
(97.4%) [33].
It is considered that submit teenagers to screening can lead to unnecessary treat-
ment of cervical precancerous lesions that have a high probability of regressing
spontaneously within 2 years of presentation. By contrast, the overtreatment is a
real risk for damage on reproductive health [34].
ACOG, ACS, USPSTF Guidelines recommend to start at age 21, with different
indications and case by case in immunocompromised patients, unreliable girls,
multiple partners, pregnant patients, HIV positive, adolescent exposed in utero to
DES [35].
Given the above considerations, there are no common protocols for the treatment
of intraepithelial lesions in adolescents; however, in cases where the cytological
Fig. 14.8 Condyloma of

the portio
Table 14.2 Protocols for the treatment of intraepithelial lesions in adolescents
• HPV Test is not appropriate

• Colposcopy immediate is not appropriate
Repeat pap test after 12 months
< HSIL (fig.7) >HSIL (fig.8)
Pap test after 12 months

COLPOSCOPY
Negative >ASC
Return to Recommendations
screening
*Counselling in STDs
*Screening for Chlamidia-Gonorrhoea-HIV
*Counselling in contraception
*Invite anti-HPV vaccination
examinations were performed, procedure for higher risk assessments is reported in

Table 14.2 [36].
In the case of HSIL, referral of all to colposcopy is recommended. If CIN1 is
diagnosed, follow-up with cytology is recommended at 12-month intervals. If CIN2
is diagnosed, observation is also recommended with 6-month intervals using cytol-
ogy and colposcopy for up to 2 years. If CIN2 is persistent at 2 years, then treatment
is recommended [37].
Prevention and Profilaxis

The WHO recommends a comprehensive and integrated approach for the pre-
vention and control of uterine cervical cancer. The set of recommended
actions includes measures that should be taken during the course of life, start-
ing from education for informed sexuality. Primary prevention begins with
vaccination against HPV in girls aged 9–13 years, that is, before they become
sexually active.
Vaccines against HPV are composed of purified proteins derived from cer-
tain types of HPV, which form virus-like particles associated with adjuvant
substances. Vlp mimic the viral capsid, but do not contain genetic material of
the virus; therefore, they are able to induce a specific antibody response for
HPV type, depending on the protein used, but are not able to cause infections.
232 G. Di Paolo
Two kinds of preventive vaccines are available against HPV: bivalent and
quadrivalent; both protect against HPV 16 and 18, which are responsible for
about 70% of cervical cancers. The quadrivalent vaccine also protects against
HPV 6 and 11, responsible for 90% of genital warts. Both vaccines have
shown a certain level of cross-protection to other oncogenic HPV types, but
not complete towards oncogenic genotypes. In June 2015, it was authorized in
Europe a new 9-valent vaccine, which in addition to HPV 6, 11,16, and 18,
protects against other oncogenic serotypes 5 (31, 33, 45, 52 and 58).
Many clinical studies have described a good safety profile of these vac-
cines [38], and in particular it has not found an increased risk of developing
autoimmune diseases in vaccinated subjects [39].
The efficacy of vaccination does not seem to be significantly reduced by
the passage of time and various meta-analyses have shown that, in countries
where 50% of women have been vaccinated, there is a notable reduction in
HPV 16–18 infections (68%) and in ano-genital condilomatosis in the pre-
and post-vaccination period in girls between 13 and 19 years of age [40].
The bi-valent, quadrivalent, or 9-valent vaccine is recommended for
females, while the quadrivalent or 9-valent is recommended for males [41].
HPV vaccination does not replace cervical cancer screening. In countries
where HPV vaccine is introduced, screening programmes may still need to be
developed or strengthened. All women who have been vaccinated against HPV
should still follow the screening recommendations for their age groups [42].
14.9 HIV (Human Immunodeficiency Virus) Infection
The human immunodeficiency virus (HIV) is still one of the most serious infective
diseases. It is associated with a serious, permanent disease of the immune system,
which is expensive to treat and cure and which still causes a significant number of
deaths and leads to reduced life expectancy.
The incidence of HIV infection in the world is still high: it is estimated that there
is a 46–70% chance of infection following sexual intercourse with an infected part-
ner and that chance is even greater if the partner is unaware of being seropositive for
HIV. One in seven people with HIV does not know that they have been infected and
a high proportion of patients only discover that they are ill after a significant period
of time has elapsed. Consequently, there is a greater risk to their health and more
risk of them spreading the virus themselves.
HIV is only transmitted in three ways:
–– Through unprotected sexual intercourse, without using a condom (sexual

transmission)
–– Through shared use of needles and other material means of injection (transmis-
sion by blood)
–– From mother to child during pregnancy, birth, or breastfeeding (vertical transmission)
Table 14.3 Trend in means Means of infection Percentage

of transmission 2006–2015
Children infected by mother −18
(ECDC data)
Injection of drugs −38
Heterosexual intercourse +19
Sex between men +25
The data shown highlight how men who have sex with other men are dispropor-
tionately struck by HIV, as they are with other sexually transmitted infections (gon-
orrhoea, syphilis, chlamydia, and hepatitis B and C) (Table 14.3).
The probability of infection through sexual contact depends both on the charac-
teristics of the virus and on the condition of the immune system; lesions and genital
inflammation caused by the various STDs considerably increase, by about ten times,
the risk of contracting HIV and it is estimated that these interactions come into play
in at least 40% of the cases of HIV transmission. 2.8% of young people who had
been diagnosed with an STD also resulted positive for HIV against an average in the
general population of about 0.1%.
HIV screening is recommended for:
• People diagnosed with an STD

• People who have used injected drugs
• People who have had sexual intercourse with subjects who are seropositive for
HIV
• People with anamneses featuring previous sexual abuse or violence
• People originating from countries where there is a high incidence of the HIV
virus
• Women in the first 3 months of pregnancy
THE HIV TEST:
• Must be voluntarily taken without any form of coercion. Patients must not be
tested without their knowledge.
• Routine use of HIV screening (notifying patients that an HIV test will be per-
formed) is recommended in all health facilities.
• Specific written consent for HIV testing should not be requested—informed gen-
eral consent for medical treatment is considered to be sufficient.
• Positive preliminary screening tests for HIV infection must be followed by fur-
ther tests to confirm the diagnosis with certainty.
• People who are suspected of having recently contracted HIV must be immedi-
ately sent to a specialized treatment unit.
14.10 Hepatitis
Hepatitis B (HBV) and C (HCV) must still be considered diseases with serious
social impact. It is necessary to identify preventative instruments and management
techniques to better control this pathology which represents a serious public health
234 G. Di Paolo
problem, striking 400 million people around the world, of whom 95% are unaware
that they have contracted the disease.
Subjects who result as being positive from the test for hepatitis should be
informed of measures to be taken that are adequate to prevent transmission which
occurs principally by blood contact.
The campaign to vaccinate against Hepatitis B must be promoted.
14.11 The Zika Virus
The principal means of transmission of the Zika virus is by means of the bite of the
Aedes mosquito. It has recently been demonstrated that sexual transmission of the
virus is possible and very common [43].
A study on the persistence of the Zika virus in bodily fluids has demonstrated
that the virus may remain in the sperm of infected men until up to 6 months after the
onset of symptoms [44].
The presence of the virus does not automatically imply a risk of infection, but the
possibility is not excluded. In order to inhibit this means of diffusion of the Zika
virus, the WHO has released new guidelines to prevent the transmission of the virus
by sexual intercourse. These guidelines are valid not only for those countries directly
affected by the epidemic, but also for those in which cases of infection could only
be imported. The document requires that both men and women abstain from sex, or
use a condom for at least 6 months, even if no symptoms are detected.
The WHO also states “presently, knowledge of the Zika virus is limited and our
guidelines will be re-examined and updated according to the latest research avail-
able” [45].
14.12 Trichomonas vaginalis
Infection by Trichomonas is a very common sexually transmitted disease; it is

asymptomatic in 50% of cases in females and 90% males. Transmission is primarily
through sexual contact; in women, the most affected parts are vagina and cervix with
occasional involvement of the urethra, Bartholin’s glands, and Skene’s glands. In
men, the infection involves urethra, prostate and seminal vesicles. The more evident
symptoms of acute trichomoniasis are leucorrhoea in significant amounts, itching,
vulvar and vaginal erythema, dyspareunia, dysuria, and inflammation of the uterus.
The gynaecological examination showed the characteristic malodorous leucorrhoea
and hyperaemia of the vaginal mucosa (Fig. 14.9); the colposcopic examination can
reveal the typical “strawberry” aspect of Tricomonas infection.
The fresh microscopic examination of vaginal secretion allows to identify the
protozoa, but the most widely used method for the diagnosis of trichomoniasis is
represented by culture in a selective medium, whose sensitivity is significantly high
(90.95%) and whose specificity is absolute (100%).
Fig. 14.9 Leuchorrhoea

and hyperemia of the
vaginalis mucosa and
portio (Trichomonas
Vaginalis)
14.12.1 Treatment
Therapy should be extended to the partner even if he has no symptoms:

• Metronidazole 2 g × os single dose
or
• Tinidazole 2 g orally as a single dose
Alternative scheme:
• Metronidazole 500 mg × 2 orally twice daily for 7 days.
Metronidazole for topical use is not recommended because it does not reach
therapeutic levels in the urethra and perivaginal glands.
236 G. Di Paolo
The prevention and control of STDs is based on the following five strategies:
• Risk evaluation, education, and counselling of people at risk of STDs, favouring
the use of preventative instruments
• Pre-exposure vaccination of people at risk of STDs, which may be prevented by
vaccination
• Identification of people with asymptomatic infections and with symptoms asso-
ciated with STDs
• Diagnosis, treatment, counselling, and follow-up of persons with an infection
• Evaluation, treatment, and counselling of the sexual partners of people infected
with an STD [3]
In dealing with adolescents, it is fundamental to facilitate access to health facilities,

to guarantee privacy, and to offer adequate space and time for effective prevention
which permits the integration of sex education even in clinical practice.
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Pregnancy in Adolescence
15
Abbreviations
ADHS Attention deficit hyperactivity syndrome

BMI Body mass index
CNS Central nervous system
EU European Union
FASD Fetal alcohol spectrum disorders
GD Gestational diabetes
HCG Human chorionic gonadotrophin
IUD Intra uterine device
IUFD Intra uterine fetal death
IUGR Intra uterine growth retardation
LARC Long acting reversible contraception
LBW Low birth weight
NICU Neonatal intensive care unit
pPROM Preterm prelabor rupture of membranes
PTB Preterm birth
SCOG Canadian Society of Obstetrics and Gynaecology
SIDS Sudden infant death syndrome
UK United Kingdom
US United States
USD United States dollar
G. Tridenti, M.D. (*) • C. Vezzani, M.D.

Department of Obstetrics and Gynaecology, Santa Maria Nuova Hospital—IRCCS,
Viale Risorgimento 80, 42123 Reggio Emilia, Italy

Although teen pregnancy is more frequent in the developing countries, it is a major

public health issue all over the world with significant medical, emotional, and social
consequences for the adolescent mother, her child, and her family [1, 2]. According
to WHO, adolescence is the period of human life between childhood and adulthood
ranging from ages 13 to 19, so adolescent pregnancy is defined as “any pregnancy
occurring among adolescent girls aged 19 or younger” [3].
Worldwide teenage gestations are mostly unplanned. They account for 16 mil-
lion births a year from ages 15 to 19 girls and one million from 12 to 15 year olds,
with also five million abortions a year, of which three millions “unsafe.”
Complications of pregnancy and delivery are still the second cause of death in ado-
lescent girls. Even if a declining pattern is ongoing in developed countries, up to
now teen pregnancies are 11% of whole births in the world. Ninety-five percent of
them occur in low–middle income countries, mostly in sub-Saharan Africa, India,
Bangladesh, and mainly in rural areas with poorly educated women. Early marriage
and childbirth are more common in developing parts of the world, leading to differ-
ent social circumstances and possibly different pregnancy outcomes [2]. With 7% of
the whole national births, the USA shows the highest rate of teen pregnancy in
Western countries, costing 9.4 billion USD a year and defined by President Clinton
in 1995: “Our most serious social problem” [4].
Three main indicators are in use to monitorize teen pregnancy:
• Teenage birth rate: the annual number of reported live births among 13–19 years
per 1000 women aged 13–19
• Teenage abortion rate: the annual number of reported induced abortions among
<20 years per 1000 women aged 13–19
• Teenage pregnancy rate: the annual number of reported teenage live births +
induced abortions per 1000 women aged 13–19. Being often unavailable, data
about miscarriages and ectopic pregnancies are not included [5]
207,000 teenage live births a year took place in EU countries in 2011, occurring
in 15/1000 of 15–19 year olds on the average. The highest birth rates were detected
in Bulgaria (46.7/1000) and the UK (25/1000) while the lowest ones were observed
in the Netherlands (5.2/1000) and Italy (7/1000), with a general decrease of 1.3%
annually since 1996. In 2011 also 160,000 induced abortions in ages 15–19 were
performed in Europe, with the highest abortion rates in Sweden, the UK, and Estonia
(20/1000) and the lowest ones in Greece, Italy, and the Netherlands (<10/1000),
with a general decline since 1996. Reliable data about teen abortion are not always
available because of different legislations among EU countries. As previously
ascertained, teenage pregnancy outcome differs across the continent with higher
abortion rates in Northern countries [6].
In Italy, teen pregnancy is a niche event, occurring in 50% cases during the first
year of intercourses. About 10,000 deliveries in minors were recorded every year
from 1998 to 2008, i.e., about 1.7–2% total Italian births (514,308 in 2013). They
are mostly grouped in Southern Italy and the main islands (Sicily and Sardinia),
with higher pregnancy rates among foreigners (www.istat.it/it/archivio/nascite). In
15 Pregnancy in Adolescence 241
2015 about 3200 teen abortions, of which 530 in foreigners, were performed legally
in Italy, i.e., 3.4% all legal abortions, with a constant declining since 2006 [7]. It was
also verified that the lower the maternal age, the higher the abortion rate [8].
Adolescent pregnancy is a very unique situation involving both social and medical
issues; its management deserves appropriate skills and devoted health caregivers.
Main risk factors of teen pregnancy are mostly socioeconomic. Belonging to a low-
income family, promiscuity, unemployment, low educational attainment, poor school
results, living in a disadvantaged neighborhood, belonging to ethnic minorities: all
these social conditions promote teen pregnancy, along with medical and behavioral
risk factors: mental deficits, early sexual debut, risky behaviors, unprotected sex. In
fact, peer pressure to engage in sexual activity, low self-esteem, low educational ambi-
tions or goals, poor information and education about sexual health, lack of access to
contraception, inconsistent or incorrect use of contraceptive methods also contribute
to adolescent pregnancy [1]. If compared with older women, smoking, drug addiction,
and alcohol misuse during pregnancy are more frequent among adolescent mothers
[9]. Teen pregnancy is mostly connected with poverty: the lower the socioeconomic
level, the higher the risk of early pregnancy [10]. It must always be kept in mind that
a strong association exists between sexual and physical abuse and early pregnancy
[11].
To sum up, “4 steps” in adolescent pregnancy may be identified:
RISKY BEHAVIORS ® TEEN PREGNANCY ® DELIVERY / ABORTION

Even if adolescent pregnancy rates are declining in the western world, a health
care provider approaching an adolescent girl seeking for medical assistance must
always be aware that she could be at risk of early pregnancy and the subsequent
practical suggestions must be considered:
• Pregnancy test: it is mandatory in cases of amenorrhea, abdominal pains, nausea,

vomiting, weight gain, urinary dysfunctions, menstrual disorders whatever sex-
ual history is reported
• First-trimester ultrasonography is necessary to check gestational age if preg-
nancy test is positive
• Careful counselling about all available options: to be supplied with a nonjudg-
mental attitude if a pregnancy is diagnosed. The gestational age being verified,
health care provider must deal with all possible choices (parenting, termination,
fostering, adoption) according to the current laws of the country
• Privacy and confidentiality should be guaranteed at most
• Close follow-up and support: they must be supplied by devoted facilities and
specialized health care providers whatever the choice is
• Multidisciplinary approach is advisable at most, considering adolescence is a
distinct physical and developmental stage in woman’s life and teen pregnancy
worldwide shows higher maternal, obstetrical, and neonatal risks. Therefore,
adolescent gestations should be managed as high risk ones. Gynecologist and
devoted midwives, social workers, psychologists, and support groups should
take care of the adolescent mothers [12, 13]
• Postpartum or post-termination contraception planning is mandatory to be

already established when the pregnancy is still in progress [14]
Abortion in adolescents is differently regulated in various countries according to

local laws; therefore, a comprehensive dissertation of its management is almost
impossible and beyond the scope of the present treatise, which is mostly focused on
the continuation of pregnancy and the connected items.
If the adolescent’s choice is parenting, it is worth stressing that teen pregnancy
entails heavy risks both for the mother and the fetus because of typical biological,
social, environmental, and behavioral features (mostly predisposing to preterm
delivery and low birth weight infants), all of which deserve special consideration.
Teen pregnancy should therefore be managed as a high risk one in programs taking
care of its unique features and concerns [15]. The subsequent typical adolescent
biological items must be carefully considered.
• Maternal age at conception: even if previous experiences highlighted adolescent

mothers aged less than 16 years to be at high risk of preterm delivery and low
birth weight neonates [16] more recent researches defined:
–– “Young maternal age” as low gynecological age (≤2 years since menarche) or
as a chronological age ≤16 years at conception or delivery
–– “Very young maternal age” as gynecological age <2 years postmenarche or as
a chronological age <15 years at conception or delivery
–– Very young maternal age was shown both to increase the risk of maternal
anemia and to have a detrimental effect on infant health and survival by rais-
ing the risk of preterm delivery and low birth weight [17]. The birthrate is
higher among older adolescents than in younger ones [18].
• Gynecologic age, mentioned above, is defined as: age at last menstrual period
minus age at menarche. Considering 2–3 postmenarchal years are required to
reach full reproductive maturation; reproductive immaturity was defined as
gynecologic age less than 3 years [19], now updated as a gynecologic age less
than 2 years. In fact, body height and pelvic development are almost complete by
2 years after menarche [17]. During this interim, a conception may occur in still
growing reproductive organs, predisposing to preterm delivery [19].
• Maternal prepregnant size, i.e., BMI, is a reliable predictor of infant size at birth,
with small mothers delivering small offsprings. Defining low prepregnant weight
as <45 kg and short prepregnant stature as <157 cm, a less than 19.8 kg/m2 BMI
reveals a thin body habitus, with an increased risk of low birth weight babies,
possibly due to a deficit in both visceral adiposity, which is a determinant of
insulin resistance, and in subcutaneous truncal adipose tissue during the first 2
postmenarchal years [16].
• Cervix length, defined as the shortest distance between the internal cervical os and
the external one, in adolescent mothers may be shorter than in older women because
of still incomplete development, thus predisposing to preterm delivery when a dis-
tance <25 mm is detected prior of 29 weeks gestation [17, 20]. Shorter cervices may
also predispose to lower genital tract infections, which are more frequent in
adolescents with a further increased risk of preterm delivery. During pregnancy,

cervical length should be verified by serial transvaginal ultrasonic scans.
• Gravidity and parity: as opposed to what happens in adults, repeated adolescent
pregnancies show a growing risk of preterm delivery [19].
• Fetomaternal competition for nutrients, occurring between the still growing
mother and her fetus, may explain the reason why pregnant teens gain more
weight during pregnancy and deliver smaller babies than older women do. The
needs of both growing mother and fetus cannot simultaneously be satisfied and a
competition for nutrients occurs between each other resulting in higher incidence
of both poor fetal growth and maternal anemia [17]. Leptin surges in the third
trimester, hyperinsulinemia, insulin resistance may lead to continuous storage of
maternal fat reserves, making less energy available for the fetus with subsequent
smaller placenta, less placental nutrient transfer, and reduced uterine/umbilical
cord blood transfer and IUGR [21].
To prevent preterm delivery and low birth weight babies, health care providers
dealing with pregnant teens must focus their attention on the below reported items:
• Gestational weight gain, defined as the difference between the last measured
weight gain in pregnancy and the reported prepregnant weight is a reliable pre-
dictor of the infant birth weight mainly in adolescents because of their typical
perimenarchal weight gain at central body areas [16].
• Past history of preterm delivery: it raises the risk of a subsequent premature birth
mainly if repeated pregnancies occur in under 18 year olds [22].
• Genitourinary tract infections are well-known preterm delivery inducers in all
ages pregnancies by favorising chorioamnionitis and by damaging the connec-
tive tissue of the cervix and the placental membranes through microbic prote-
ases, elastases, collagenases, and mucinases leading to pPROM. In pregnant
teens, the alkalinity of the peripubertal vagina may increase their susceptibility
to bacterial vaginosis; the eversion of the squamocolumnar junction of the ado-
lescent cervix may foster Chlamydia infections, of which the incidence is quite
high in this population group, ranging from 11.8 to 31% [23]. Finally, the typical
shorter cervix may enhance the ascending of vaginal organisms to the upper
uterus [19]. Besides the physiological features of pubertal status, the adolescent
sexual behaviors, typified by serial unprotected monogamous sexual relations
with low condom use, make pregnant teens frequently acquire the sexually trans-
mitted diseases fostering preterm prelabor rupture of membrane (pPROM) and
subsequent preterm delivery [24]. Besides the reported higher risk of pPROM
and preterm delivery, in pregnant teens STDs increase also the risk of HIV acqui-
sition and transmission [25].
• Trauma is the main cause of death in adolescence. Pregnant teens suffer from
accidental and non-accidental traumas more than older women do [26]. In preg-
nant teens, abdominal traumas are very frequent, rising the risk of placental
abruption and preterm delivery, making it mandatory to screen for recent traumas
in a teen pregnancy care setting [19].
As previously stated, social and demographic features, as well as behavioral and

psychological variables, are important factors in the risk assessment of a pregnant
teen and in the subsequent follow-up.
• Ethnicity is closely related to early pregnancy, with American black and hispanic
women having the highest pregnancy rates and white non-hispanic women hav-
ing the lowest ones [27]. Black race also strongly raises the risk of preterm and
very preterm deliveries both in adults and adolescent mothers (while hispanic
ethnicity does not), possibly because of increased, ethnicity-connected, suscep-
tibility to bacterial vaginosis, group B streptococcal infection, and premature
cervical effacement [28].
• Socioeconomic status plays a main role both in fostering teen pregnancies and in
conditioning their outcome, with higher rates of preterm delivery among poor
teen mothers. Some experiences showed that pregnant teenagers were more
likely to be single and to live in a rural area [2], other researches detected higher
pregnancy rates among ethnic minorities living in deprived metropolitan areas
[10], among underachievers in school and among young women with mental
health problems [29]. Very often teen mothers belong to a single-parent family
or have parents poorly interested in their education. Having a low educated
mother or being herself a teen mother increases the risk of adolescent pregnancy,
the same as being a younger sibling of an adolescent mother [30]. Unemployment
and child poverty are also strong predisposing factors, and the trend is “the lower
the deprivation rank, the higher the risk of teenge pregnancy” [31].
• Inadequate nutrition: Even if a proper nutrition is of utmost importance during
teenage because of growth and physical changes, the diet quality is usually poor
in adolescents, whose primary sources of macronutrients are often foods lacking
nutritional properties [32]. Pregnant teens show the same food preferences, eat-
ing behaviors, and lifestyle habits of their nonpregnant peers [33]. If compared
with women aged 19–64, girls aged 11–18 consume less fruits and vegetables
with higher intakes of sugar-sweetened beverages and inadequate intake of key
vitamins and minerals. Such dietary patterns are similar across highly developed
countries [34]. Adolescent girls are at particular risk of iron deficiency anemia
due to both the rapid growth in teenage and the onset of menarche [35]. The iron
needs linked to adolescence coupled with the increased iron demand in preg-
nancy makes pregnant adolescent particularly vulnerable, and iron deficiency is
aknowledged to be implicated in adverse birth outcomes such as prematurity and
low birth weight [32]. As well known, good pregnancy nutrition plays an impor-
tant role on birth outcomes, fetal growth, and infant survival. Nutritionl needs
change during the course of pregnancy with increasing requirements for several
micronutrients as the pregnancy progresses [36]. Conversely, pregnant adoles-
cents were shown to have intakes of energy, iron, folate, calcium, Vitamin E, and
magnesium below the dietary recommendations [37, 38]. If compared with older
teens, “very young adolescents” (under 15 years or under 2 years gynecological
age) may be at even greater nutritional risk due to competing growth needs
between mother and fetus [17]. Smoking teen gravidas and those from deprived
backgrounds may also be at greater risks of nutritional issues [39, 40]. Compliance
for supplements may be low in pregnant teens [32].
• Substance abuse: According to large cohort studies, tobacco smoking, drugs, and
alcohol misuse are more frequent among teen mothers than in pregnant women
aged 25–30 [10]. Sigarette smoking during the first trimester entails an increased
risk of miscarriage and labio-palatoschisis while smoking during the whole preg-
nancy (the same as heavy second hand smoke) implies higher incidences of pre-
term delivery, low birth weight babies SIDS and future smoking offsprings,
mainly if they are females. Attention-Deficit/Hyperactivity Disorder (ADHD)
and asthma are also more frequent among children of smoking pregnant teens.
Smoking reduction programs for pregnant adolescents were more successful
when smoking partners are also involved [41]. Alcohol misuse is epidemic among
adolescents, and it is quite common also among pregnant teens. Both alcohol
moderate daily assumption and occasional drunknesses during the first trimester
raise the risk of miscarriage, intra uterine fetal death, and a range of lifelong
physical, cognitive, and behavioral birth defects, such as IUGR, microcephaly,
facial dismorphologies (short palpebral fissures, thin upper lip, smooth filtrum),
and various central nervous system dysfunctions, all grouped under the umbrella
name of fetal alcohol spectrum disorders (FASD) [42, 43]. Considering FASD
are mostly due to a fetal alcohol exposure between the sixth and 12th week of
gestation, they are only partially preventable at the first antenatal visit.
International guidelines recommend temperance during the first trimester of ges-
tation but even in the subsequent trimesters a security threshold is not specified
because of individual alcohol metabolization [41]. Pregnant teens may be mul-
tiple illicit substances addicts, each one with different dangerous effects (sum-
marized in the Table 15.1), but all of them sharing a common increased risk of
preterm delivery and IUGR.
• History of childhood abuse: A history of sexual and physical abuse places female
adolescent at increased risk of becoming pregnant, fostering early sexualization,
initiation, sexual risk-taking behaviors, and promiscuity [11]. In the main, expo-
sure to all types of abuse increases the likelihood to start intercourses at early age
and promotes low self-esteem and association with deviant peer groups: all fac-
tors leading to premature pregnancies [1]. The strength of this association varies
with abuse type. Higher risk of adolescent pregnancy was verified following
sexual and physical abuse but not in cases of emotional abuse and neglect. The
co-occurrence of both physical and sexual abuse was even stronger than any
single kind of abuse, with a fourfold increased risk of early pregnancy [11].
Among previously abused adolescents pregnancy may be not unplanned: a desire
to escape from an abusive or dysfunctional family and to create a new family
environment may lead to early pregnancy [44]. Previously abused pregnant ado-
lescents are more likely to be cigarette smokers and alcohol or illicit substances
addicts. They are also more often sexually promiscuous and involved in coercive
sex, with higher risks of STDs and injury-mediated preterm delivery [16, 19].
Teen mothers who have been victims of abuse show higher risk of seeking late
antenatal care, poorer obstetrical outcomes, increased neonatal morbidity and of
Table 15.1 Effects of prenatal exposure to abuse substances [41]

Other
Effects on fetus Neonatal Neurodevelopmental long-distance
Substance and pregnancy effects disorders effects
Cannabis and Ectopic Risk of SIDS Short term and visuo- Higher risk
cannabinoids pregnancy, spatial memory defects of tobacco
IUGR, preterm Defective verbal and and cannabis
delivery attentive abilities smoking
Hyperactivity offsprings
Cocaine Acute Low body Higher sensitivity to Overweight
hyperthermia length and stressors in babyhood
weight
Altered placental Risk of Hyperexcitability
vessels with necrotizing
preeclampsia and enterocolitis
abruptio
placentae
IUGR, preterm Urogenital and Cognitive disorders Low linear
delivery cardiac Teen impulsiveness growth in
anomalies second
childhood
Amfetamine Hyperthermia Low birth Higher emotivity
and derivates weight
IUGR Low APGAR Anxiety and depression in
score childhood
Preterm delivery Low motor ADHS
ability Low verbal memory
Opioids Abruptio Neonatal Visual defects
placentae due to withdrawal
untreated syndrome
withdrawal
IUGR SIDS Neurodevelopmental and
Preterm delivery behavioral disorders
Inhalants: Miscarriages Skeletal Neurodevelopmental
gases, solvents, anomalies delay
aerosols, IUGR CNS
nitrites anomalies
committing sexual abuse during their own child’s life [45–47]. Moreover, if a
history of previous sexual abuse doubles, the risk of adolescent pregnancy in a
girl, a fivefold increase of pregnancy involvement was verified in previously
abused boys [48]. Sexual abuse and violence before and during pregnancy should
routinely be asked in an adolescent pregnancy setting [49].
• School dropout: Undereducation is a sign of a set of psychosocial and medical
risk factors; in fact, recreational drugs addiction, alcohol abuse, deviant behavi-
urs, preterm delivery are more common among pregnant teens who dropout of
school. By leaving school, these girls also loose an important source of support
which could help them to develop the sense of mastery required to face mother-
hood [16, 19].
• Mood disorders: Psychopathology in teenagers is a risk factor for early preg-

nancy. Sixteen to 44% pregnant teens show depressive symptoms which worsen
between the second and the third trimester, with an incidence twice as high as
among adult gravidas and nonpregnant adolescents [50, 51]. Adolescent perina-
tal depression is strongly associated with low socioeconomic status and lacking
social support [52]. Furthermore, previous experiences revealed postpartum
depression in half adolescent mothers, i.e., twice the rate of adult mothers [53].
If untreated, maternal depression is associated with adverse maternal, neonatal,
and childhood outcomes, with higher incidence of preterm delivery, SGA infants
and behavioral and cognitive disorders in children as well. Postpartum depres-
sion, unresponsive mothering, and rapid repeated pregnancy often occur in
depressed pregnant teens [54, 55] with frequent postpartum smoking, alcohol
misuse, and substance abuse [56].
Adolescent pregnancies have a higher risk of adverse outcomes [57] and besides
age-related risk factors pregnant teens show typical maternal, obstetric, and neona-
tal complications during gestation and at delivery, of which it is worth mentioning:
• Anemia and nutritional deficiencies: Because of feto-maternal competition for

nutrients and increased postmenarchal needs anemia is very frequent among
pregnant adolescents, being detected in 50–66% cases [58]. Besides the above-
mentioned deficiencies of micronutrients, because of mostly unplanned gesta-
tions, precoceptional counselling and folic acid supplementation are often missed
in pregnant teens, whose age implies a slowly higher risk of spina bifida. Eating
habits, cigarette smoking, alcohol consumption, and some gastrointestinal dis-
eases, such as celiac disease, atropic gastritis, Crohn’s disease, and ulcerative
colitis, may impair the intestinal absorption of folate, the same as the administra-
tion of trimethoprim, pyrimethamine, antiepileptic drugs, aminopterin, metho-
trexate, sulfasalazine, and isotretinoin [41]. All the above-mentioned clinical and
behavioral situations, and also MTHFR gene polymorphism, require an imple-
mented 5 mg daily folic acid supplementation instead of the usually recom-
mended 400 μg daily administration [59]. Furthermore, because of poor outdoor
activities, Vitamin D blood levels were shown to be low in many adolescents,
mainly if they are black, vegan, on a low fat diet, overweight, or obese. Type 1
diabetes, inflammatory bowel diseases, liver diseases, cystic fibrosis, African or
Southern Asian ethnicities, long lasting treatments with heparine, isotretinoin,
glucocorticoids, antituberculous, and antiepileptic drugs may also lower Vitamin
D availability, and its deficiency could promote preeclampsia and impair the
skeletal and dental development of the fetus. Daily Vitamin D 100 UI, equal to
10 μg, is needed in pregnancy. Either daily 15 minutes sun exposure of arms and
face or Vitamin D supplementation are recommended in pregnancy [60].
• Eating habits and BMI: Teen pregnancies may occur in girls suffering from eat-
ing disorders while they improve their food supply. A low BMI, as defined by
proper age-related diagrams, raises the risk of LBW newborns and preterm deliv-
ery due to pPROM. Eating habits must be strictly monitored in pregnant teens,
Table 15.2 Total and average physiologic weight gain related to preconceptional BMI
Second and third trimester
Preconceptional BMI (kg/m2) Total weight gain average weight gain (kg/week)
<18.5 → underweight 12.5–18 0.51
18.5–24.9 → normal weight 11.5–16 0.42
25–29.9 → overweight 7–11.5 0.28
>30 → obesity 5.9 0.22
Dei and Bruni [41]
considering also a high preconceptional BMI and high-fat diets raise the risk of
both macrosomia and preeclampsia [41]. Total and average physiologic weight
gain related to preconceptional BMI is reported in Table 15.2.
• Insufficient prenatal care: if compared with older pregnant women, adolescents
were shown to start their prenatal care significantly later in pregnancy, with
delayed or missed first trimester antenatal visits and also significantly lower
attendance rate of prenatal classes [2, 46]. Reasons for delay in seeking care lie
on lacking knowledge about the relevance of prenatal care and about the conse-
quences of its missing. Previous violence, desire to hide pregnancy, doubts about
continuation, concerns about lack of privacy or judgmental attitudes from health
care providers, financial problems may be further reasons behind the delay.
Absent or delayed prenatal care worsens maternal, obstetrical, and neonatal out-
comes [61].
• Preeclampsia and hypertensive disorders of pregnancy: available data about
their incidence in teens are controversial. Some studies reported a higher inci-
dence than in adults, possibly connected to the reproductive and physiologic
immaturity of pregnant adolescents [16, 19, 62]. Other experiences do not dem-
onstrate any difference [46] or even showed reduced rates after potential con-
founders being controlled [9]. Very common risk factors of preeclampsia in teens
are nulliparity and first pregnancy with a partner [41]. Screenings of preeclamp-
sia are available at first trimester by combining blood pressure assessment, ultra-
sonography, and seric PAPP-A levels at the second trimester by performing
Doppler ultrasonography of maternal uterine arteries.
• Gestational diabetes: in pregnant teens, lower rates of GD were detected than in
adults [9, 63].
• Congenital anomalies are more common in adolescent pregnancies, with higher
rates of CNS anomalies (anencephaly, spina bifida, hydrocephaly, microceph-
aly), gastrointestinal anomalies (gastroschisis, omphalocele), and musculoskel-
etal anomalies (cleft lip, cleft palate, polydactily, syndactaly) [64], possibly due
to pre- and postconceptional risky behaviors or to nutritional deficiencies [41]. A
careful second trimester ultrasonographic screening of fetal anomalies must be
supplied.
• Molar pregnancy: complete hydatidiform mole shows a biphasic trend, with
higher incidence at both extreme reproductive ages. In under 20 year olds, a
sevenfold higher rate was detected (4–6/1000 cases), which further worsens in
oriental girls. On the contrary, invasive mole and choriocarcinoma are very rare
in teens. Nausea, vomiting, bleedings, pelvic pains, and signs of hyperthyroidism

are common symptoms but the diagnosis is mostly made by β-HCG evaluations,
showing much higher serum levels than expected according to gestational age
(>100,000 UI), and ultrasonography, with the typical “snowstorm pattern.”
Suction curettage is the treatment of choice and subsequent β-HCG monitoring
is mandatory [41, 65].
• Preterm delivery (PTB) and IUGR are the main issues dealing with adolescent
pregnancies. Higher risks of PTB (<37 weeks), very PTB (<32 weeks), and
extremely PTB (<28 weeks) are reported in pregnant teens, as well as LBW
babies (<2500 g), very LBW babies (<1500 g), IUGR (<3rd centile for gesta-
tional age), stillbirths, NICU admissions, and neonatal deaths [9, 61]. Typical
teen risk factor of PTB and IUGR are summarized in Table 15.2. The younger
the adolescent in terms of chronologic and gynecologic ages, the higher the
rate of preterm labor and delivery. Advisable interventions are based on close
follow-up, appropriate weight gain, cervical cerclage (when suggested by the
clinical picture), screening of urogenital infections, psychologic and social
support, screening of sexual abuse and careful timing of delivery [19] the ges-
tational age being verified, a careful follow-up of fetal growth is mandatory in
the third trimester. Serial biometric ultrasonography with also maternal and
fetal Doppler velocimetry should be preferred to symphysial fundal height
measurements [41].
• Multifetal pregnancies are a further risk factor of PTB and IUGR. Accurate esti-
mates of multiple pregnancies in adolescents are lacking but a threefold higher
rate was detected in black girls, possibly because higher baseline FSH levels in
black women. Adolescent multiple gestations carry an even higher incidence of
preterm birth (81%), IUFD and IUGR than teen singletons and adult twin preg-
nancies (Table 15.3). Moreover, most infants are LBW ones. [66].
Table 15.3 Risk factors of preterm birth and IUGR

Risk factors of preterm birth Risk factors of IUGR
Maternal age <16 years Low maternal height and weight
Gynecologic age <2 years Low preconceptional maternal BMI
Parity Low central fat stores
Previous preterm deliveries Still ongoing maternal growth
Urogenital infections Gestational hypertension
Traumas Defective placentation
Black race Smoking during first trimester
Poverty Missed folic acid supplementation
Smoking and substance abuse Maternal DHA and Vitamin D deficiencies
Lacking perinatal cares Anemia
Poor school attendance High caffeine intake
Previous sexual abuse Malaria
Stress and depression Hyperthyroidism
Poor social support Disadvantaged socioeconomic status
Multiple pregnancy Domestic violence and sexual coercion
Steven-Simon et al. [19], Dei and Bruni [41]
Early puberal pelvis

Justominor pelvis Age 12
Age 9
Late puberal pelvis Mature gynecoid pelvis

Age 15 Age 18
Fig. 15.1 Reshaping of the pelvis at puberty [67]
Labor and delivery have peculiar features in teenage, requiring appropriate care
and management. The adolescent pelvis, mainly at very young ages, is incompletely
developed, transversely narrowed and anthropoid shaped, with small capacity. A
reshaping of the pelvic inlet and outlet takes place during puberty, with a tranverse
enlargement leading to a rounded mature, gynecoid-shaped pelvis (Fig. 15.1). At
the same time, a remodeling of the subpubic arch occurs, from the pointed arch of
the immature pelvis to the rounded arch of the mature gynecoid pelvis (Fig. 15.2).
The closer is the menarche, the less adequate is the pelvis to deliver [67].
Furthermore, during pregnancy the still growing pregnant adolescents show a three-
fold bigger bone mineral impoverishment than adult gravidas. This accelerated
bone mineral loss is not fully counterbalanced by the physiologic increase in cal-
cium absorbtion normally occurring in pregnancy. This event reveals the continuing
unmet maternal skeletal needs during pubertal development and growth, further
amplified by fetal skeletal mineralization. Osteopenia is rather frequent in pregnant
teens, while osteomalacia is more common in adult multiparas and osteoporosis
typifies other clinical pictures [68].
According to Friedman’s curve, the average labor in adolescents progresses
slower than in older gravidas. All steps of both cervical dilation and fetal descent are
significantly delayed, as depicted in Fig. 15.3 by matching adolescent and adult
Friedman’s curves [69]. Teen parturients in labor show slower rates of dilation and
descent, longer latent, active and deceleration phases, and longer second stages;
therefore, oxytocic drugs are more often required. Even if macrosomia is rare in
adolescence, teen labors associated with macrosomic fetuses display a significantly
Justominor pelvis Early puberal pelvis

Age 9 Age 12
Late puberal pelvis Mature gynecoid pelvis

Age 15 Age 18
Fig. 15.2 Reshaping of the pelvis at puberty [67]
10
8
Cervical dilatation (cm)
6 Age 20–29
Age <20
4
0
0 2 4 6 8 10 12 14 16
Time in labor (hour)
Fig. 15.3 Plot of cervical dilation vs. elapsed time in teens and adults [60]
longer active phase and a higher incidence of distocias. Very likely, the still imma-
ture pelvis increases the risk of abnormal labor progression and cephalopelvic dis-
proportion [67]. In contrast with older woman, adolescents revealed lower rates of
assisted delivery and cesarean section, varying from 2 to 14% [70]. Because of the
higher incidence of preterm delivery, IUGR, SGA neonates, abnormal labor, IUFD,
and the higher neonatal mortality (inversely correlated with maternal age), teen
gravidas should deliver in tertiary care hospitals [67].
Postpartum deserves special considerations in teenage mothers because of its
proper risk factors. It is a period of female life characterized by psychological vul-
nerability for every woman and mainly for adolescent mothers, who may have more
difficulties in fulfilling their maternal role. Teen mothers are more likely to suffer
Teen pregnancy : the SCOG guide lines-1

TEEN PREGNANCY FEATURES SCOG GUIDE LINES
Proper and higher fetomaternal 1-Prenatal care must be adapted to teenagers
risks are present offering multidisciplinary care at one site
Confidentiality is required 2-Health care providers should be sensitive to

teen needs during pregnancy and at delivery
Prenatal care is lacking or delayed

3-Teenage pregnancy is a high risk one and it
Poor parenting skills in teen mothers should be adequately managed
Lacking role of fathers and partners 4-Fathers and partners should be involved at
most in pregnancy care and infant education
Gestational age is often uncertain 5-A first trimester ultrasound is mandatory
Teens are doubtful and confused 6-Counsel about all pregnancy outcome options
(abortion, adoption parenting)
Higher risks for STDs and bacterial 7-Test and treat for STDs and BV at presentation,
vaginosis (BV) at 3°trimester and pospartum
30
J Obstet Gynecol Can 2015; 37(8):740-756
Fig. 15.4 Synopsis of the SCOG Adolescent Pregnancy Guidelines - 1
Teen pregnancy: the SCOG guidelines-2

TEEN PREGNANCY FEATURES SCOG GUIDE LINES
Higher rates of smoking, alcohol
and substance abuse 8- Repeated screening for alcohol use,
substance abuse and violence recommended
Sexual abuse and IPV is common
9- Repeated screening forand treatment of

Depression is frequent, mainly in 2° mood disorders in pregnancy irecommended
and 3°trimesters and postpartum
10- Make nutritional assessment, with

Anemia and undernutrition are vitamin and food supplementation; treat
common anemia, LBW ; optimize weight gain
Risk of preeclampsia is conflicting 11- Usual care for preeclampsia recommended
Rates of GDM are lower 12- Testing for GDM is anyway appropriate
13- US anatomical scan at 16-20 w

PTB, LBW,IUGR, stillbirths, congenital
14- US screening for IUGR at 32-34 w
anomalies are more common
15- more frequent visits in the 2°& 3°trimester
to screen for preterm labour and preterm birth
31

Teen pregnancy: the SCOG guidelines-3

TEEN PREGNANCY FEATURES SCOG GUIDELINES
Higher rates of vaginal deliveries, 16- Multidisciplinary peripartum care in

Lower rates of assisted vaginal hospital involving social care, support
deliveries and CS for breastfeeding and lactation, and
children’s aid services when warranted
High risk of rapid repeated pregnancy 17- Postpartum care should include a focus
so the provision of contraception is on contraceptive methods, mainly LARC, to
crucial begin before delivery
Lower rates of initiation and 18- Breastfeeding should be recommended

continuation of breastfeeding and sufficient support should be given.
Risk of poor mothering, postpartum 19- Postpartum care programs are necessary
depression & rapid repeat pregnancy to support adolescent families, to improve
parenting and breastfeeding, to screen and
treat postpartum depression, to increase birth
Intervals, to decrease unintended pregnancies.
Recommendations from 20 to 23 are devoted to pregnant adolescents belonging

to Aboriginal communities living in rural and remote regions of Canada
32
from depression, to dropout from school, and to have low educational attainment, to
live in poor housing, to be unemployed or low paid, and to require social assistance.
They may be abandoned by the partner and lack family support. The child of a teen
mother is more likely to live in poverty, to grow up without a father, to be negleted
or abused, to attain poor school results, to be involved in drug and alcohol addiction,
crime, or abuse and, last but not least to become a teen parent itself [1, 41, 71].
Health caregivers dealing with adolescent mothers in postpartum period should
focus their attention on the following main issues.
• Breastfeeding: Teen mothers have a lower initiation and continuation rate of

breastfeeding than adult women [72], possibly due to multiple socioeconomic
factors. Age, race, educational level, marital status, and economic conditions
may be determinant, as well as poor knowledge and lack of breastfeeding sup-
port from family, friends, and partner. Social care and support should be given to
foster breastfeeding for at least 6 months, according to joint WHO/UNICEF
global recommendations for optimal infant feeding [73]. Proper information
should be given to drug-addicted teen mothers about substances excreted in
breast milk [41].
• Nutrition: It should be properly addressed to support breastfeeding teen mothers
whose calorie needs exceed pregnancy ones. Hundred grams of breast milk require
90 kcal energy intake and a daily 2.7 L watery intake is needed. To maintain mater-
nal bone mass, adequate nutritional calcium intake is recommended [41].
• Depression: It is very frequent in postpartum. In teen mothers, it is highly more

common than in adult ones, influencing parental behaviors and intefering with
maternal sensitivity and discipline. Significant depressive symptoms were reported
in up to 45% of teen mothers after 1 month and till 1 year from delivery [74].
Multiple pathogenetic factors are involved, mostly based on previous depressive
features, obstetrical complications, stressing events during pregnancy, or prolonged
absence of the child because of NICU hospitalization. First pregnancy, difficult
breastfeeding, lacking partner, conflicting family and intimate relationships, domes-
tic violence, lacking social support, sense of neglect, and parenting stress may pro-
mote the onset of postpartum depression, affecting both the teen mother and her
developing infant [41, 75]. In fact, depressive symptoms in adolescent mothers are
associated with problem behavior and poorer academic achievements in their off-
springs, from toddlehood through adolescence [51]. Indeed, lower rates of postpar-
tum depression were observed when family or partner’s support is available while
lacking support increases stress and depression, raising the risk of abuse, neglect,
and violence [76]. Early diagnosis and treatment of teen postpartum depression is
recommended. Screening of postpartum depression is therefore mandatory and
variations of the Edinburgh Postnatal Depression Scale were shown to be accurate
screening tools [77]. Postpartum care programs, social workers, and local midwives
should be available to provide the adolescent mother with the support she needs.
• Education: Fostering the continuity of education of pregnant teens and teen
mothers is the main goal to avoid subsequent social marginalization, poverty, and
neglect. Proper laws and school programs should be available [71].
• Rapid repeated pregnancies, i.e., within 2 years from delivery, occur in 35%
cases, two-third of them are unplanned and they are more frequent among ethnic
minorities. School attendance and living alone or with a parent as opposed with a
partner are protective factors against rapid repeated pregnancies [78]. Adolescent
mothers should be informed that lactation is not a reliable contraceptive method
and a barrier method may be employed at any time. The provision of contracep-
tive options is crucial in postpartum care and contraceptive counselling should be
started during pregnancy. Oral contraception and a subdermal contraceptive
implant may be supplied 6 weeks postpartum while an IUD may be inserted 2
months after delivery [41]. In teen mothers, LARC methods, such as subdermal
implant, Depot Medroxyprogesterone Acetate (not available in Italy), and IUDs,
are a far better prevention of repeated pregnancies than are shorter term methods
such as oral contraception, contraceptive patches, or barrier methods [79]. LARC
methods are first choice in teens and they should be suggested after delivery
before the patient is dismissed from hospital. A non-LARC method could be sup-
plied temporarily and barrier methods are always advisable to prevent STDs [80].
15.1 Final Remarks
Teen pregnancy is risky for both the mother and the fetus. While approaching a
pregnant adolescent, all possible outcomes must be discussed with a nonjudgmental
attitude, assuring privacy and confidentiality. Whatever the choice is, a very close
follow-up must be provided, preferably by a multidisciplinary team. If parenting is

choosen, appropriate nutrition and weight gain should be strictly monitored. PTB,
IUGR, STDs, substance abuse, and sexual abuse should be screened. Delivery in a
tertiary care hospital is recommended. Postpartum depression should always be
screened and treated. Prevention of rapid repeated pregnancies is mandatory by
early contraceptive counselling. LARC methods are the first choice in adolescents.
Appendix 1: WHO Guidelines for Developing Countries
Considering early childbearing mostly occurs in developing countries, it also

reflects broader forms of social and economic marginalization of girls. To prevent
early pregnancy, WHO suggests the following guidelines:
• Prevent early marriage → by extending school age for girls

→ by prohibiting marriages in under 18 year olds
• Foster prevention → with sex education in school
→ in connection with sexual health services
• Improve contraception → by including contraception in sex education
→ by organizing “youth friendly” health services
→ by supplying contraception after deliveries or
abortions
→ by fostering tolerant laws and policies
• Punish forced sex → by banning it by law
→ by making the perpetrator punishable
• Reduce unsafe abortion → with educational campaigns
→ by admitting teens to family planning services
→ by providing post abortion care and contraception
• Supply proper pre- and post-natal cares → with laws taking care of adolescents
World Health Organization [81]
Appendix 2: SCOG Adolescent Pregnancy Guidelines
In August 2015, the Canadian Society of Obstetrics and Gynecology published a

guideline about adolescent pregnancy which still may be considered the most com-
prehensive and updated one. Published on the Canadian Journal of Obstetrics and
Gynaecology [12], it has been summarized in the following pictures:
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Good Practice in

Anna Maria Fulghesu

Good Practice in Pediatric

ISBN 978-3-319-57161-4 ISBN 978-3-319-57162-1 (eBook)

Library of Congress Control Number: 2017954378

© Springer International Publishing AG 2018

Printed on acid-free paper

This Springer imprint is published by Springer Nature

Cagliari, Italy Anna Maria Fulghesu

13 Sexual Abuse and Genital Trauma���������������������������������������������������������� 193

Anna Maria Fulghesu is a medical doctor specializing in obstetrics and gynecol-

Vulvovaginal complaints account for 80–90% of outpatient pediatric gynecologic

C. Vezzani, M.D. • G. Tridenti, M.D.

© Springer International Publishing AG 2018 1

airways is also possible through autoinoculation and occasionally hematic spread

Nonspecific vulvovaginitis refers to vulvovaginal irritation without an identifi-

(Streptococcus pyogenes), Haemophilus influenzae, Streptococcus and

1.4 Physical Examination and Diagnostic Testing

The examination of the child presenting with gynecologic complaints should

• Vulvitis: it is the inflammation of the vulva characterized by hyperemia and other

Vulvitis and vulvovaginitis may exhibit different clinical feature:

• Symptoms (with or without signs)

case has to be taken into account, is often indistinguishable by genital examination

Fig. 1.1 Streptococcus

vaginalis can be identified in vaginal secretions by wet mount examination, cul-

1.4.1 Vulvar Lesions

As symptoms of vulvovaginitis, vulvar dermatosis, and systemic disease with vulvar

Table 1.1 Primary and secondary skin lesions

1.4.1.1 Skin Colored Lesions

1.4.1.2 Red Patches and Plaques

Fig. 1.2 Atopic dermatitis

1.4.1.3 Red Papules and Nodules

1.4.1.4 White Lesions

Fig. 1.3 Lichen sclerosus

Fig. 1.4 Lichen sclerosus

1.4.1.5 Dark-Colored Lesions

1.4.1.7 Erosions and Ulcers

Fig. 1.5 Herpes Simplex

Epstein Barr virus (mononucleosis), Cytomegalovirus, Influenzae viruses, and

1.4.2 Labial Adhesions

Although not included in the classification described above, agglutination of labia

Fig. 1.6 Labial adhesions

1.5 Management of Vulvovaginitis

Most cases of nonspecific vulvovaginitis resolve by following hygiene education

–– Wiping front to back after using the toilet

Table 1.2 Treatment of specific vulvovaginal infections

–– Vulva and perianal area should be let dried avoiding rubbing

If symptoms are mild, using an emollient cream or ointment may be useful. In

1.6 Recurrent Vulvovaginitis

If vulvovaginitis persist despite lifestyle changes and first-line treatment, it is impor-

AMH Anti-Mullerian hormone

M. Dei, M.D. (*)

© Springer International Publishing AG 2018 19

2.1 Definition and Pathogenesis

We define a delayed puberty (DP), warranting a diagnostic evaluation, as:

1 . Lack of breast development by age 13

Cagliari, Italy Anna Maria Fulghesu

13 Sexual Abuse and Genital Trauma�� 193

1.4 Physical Examination and Diagnostic Testing

1.4.1 Vulvar Lesions

1.4.1.1 Skin Colored Lesions

1.4.1.2 Red Patches and Plaques

1.4.1.3 Red Papules and Nodules

1.4.1.4 White Lesions

1.4.1.5 Dark-Colored Lesions

1.4.1.7 Erosions and Ulcers

1.4.2 Labial Adhesions

1.5 Management of Vulvovaginitis

1.6 Recurrent Vulvovaginitis

2.1 Definition and Pathogenesis

2.1.1 Hypogonadotropic Hypogonadism

2.1.2 Organic CNS Pathologies

2.1.4 Gh Deficiency

2.1.5 Constitutional Delay of Growth and Puberty

Table 2.4 Chronic diseases Chronic liver diseases, alpha1-antitrypsin deficiency,

2.2 Diagnostic Workup

2.3 Therapeutic Approaches

3.1 Embryology Development

3.2 Etiology of Genital Malformations

3.4 Classification Systems of Genital Malformations

3.5 Diagnosis of Genital Malformations

3.6 Symptomatic Genital Malformations

3.6.1 Imperforate Hymen

3.6.2 Vaginal Atresia (Class I-a ASRM)

3.6.3 Cervical Agenesis/Atresia (Class I-b ASRM)

3.6.4 Unicornuate Uterus (Class II ASRM)

3.6.5 Didelphys Uterus (Class III ASRM)

3.6.6 Transverse Vaginal Septum

3.6.7 Longitudinal Vaginal Septum

3.7 Asymptomatic Genital Malformations

3.7.1 Vaginal Agenesis (Class Ie ASRM)

3.7.2 Bicornuate Uterus (Class IV)

3.7.3 Septate Uterus (Class V)

3.7.4 Arcuate Uterus (Class VI)